Honey as a topical treatment for wounds

  • Comment
  • Review
  • Intervention

Authors


Abstract

Background

Honey is a viscous, supersaturated sugar solution derived from nectar gathered and modified by the honeybee, Apis mellifera. Honey has been used since ancient times as a remedy in wound care. Evidence from animal studies and some trials has suggested that honey may accelerate wound healing.

Objectives

The objective was to determine whether honey increases the rate of healing in acute wounds (e.g. burns, lacerations) and chronic wounds (e.g. skin ulcers, infected surgical wounds).

Search methods

For this first update of the review we searched the Cochrane Wounds Group Specialised Register (searched 13 June 2012); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5); Ovid MEDLINE (2008 to May Week 5 2012); Ovid MEDLINE (In-Process & Other Non-Indexed Citations 12 June 2012); Ovid EMBASE (2008 to 2012 Week 23); and EBSCO CINAHL (2008 to 8 June 2012).

Selection criteria

Randomised and quasi-randomised trials that evaluated honey as a treatment for any sort of acute or chronic wound were sought. There was no restriction in terms of source, date of publication or language. Wound healing was the primary endpoint.

Data collection and analysis

Data from eligible trials were extracted and summarised by one review author, using a data extraction sheet, and independently verified by a second review author.

Main results

We identified 25 trials (with a total of 2987 participants) that met the inclusion criteria, including six new trials that were added to this update. In acute wounds, three trials evaluated the effect of honey in acute lacerations, abrasions or minor surgical wounds and 12 trials evaluated the effect of honey in burns. In chronic wounds, two trials evaluated the effect of honey in venous leg ulcers, and single trials investigated its effect in infected post-operative wounds, pressure injuries, cutaneous Leishmaniasis, diabetic foot ulcers and Fournier's gangrene. Three trials recruited people into mixed groups of chronic or acute wounds. Most trials were at high or unclear risk of bias. In acute wounds, specifically partial-thickness burns, honey might reduce time to healing compared with some conventional dressings (WMD -4.68 days, 95%CI -4.28 to -5.09 days), but, when compared with early excision and grafting, honey delays healing in partial- and full-thickness burns (WMD 13.6 days, 95% CI 10.02 to 17.18 days). In chronic wounds, honey does not significantly increase healing in venous leg ulcers when used as an adjuvant to compression (RR 1.15, 95% CI 0.96 to 1.38), and may delay healing in cutaneous Leishmaniasis when used as an adjuvant to meglumine antimoniate compared to meglumine antimoniate alone (RR 0.72, 95% CI 0.51 to 1.01).

Authors' conclusions

Honey dressings do not increase rates of healing significantly in venous leg ulcers when used as an adjuvant to compression. Honey may delay healing in partial- and full-thickness burns in comparison to early excision and grafting, and in cutaneous Leishmaniasis when used as an adjuvant with meglumine antimoniate. Honey might be superior to some conventional dressing materials, but there is considerable uncertainty about the replicability and applicability of this evidence. There is insufficient evidence to guide clinical practice in other types of wounds, and health services may wish to consider avoiding routine use of honey dressings until sufficient evidence of effect is available.

Résumé scientifique

Le miel comme traitement topique des plaies

Contexte

Le miel est une solution visqueuse, sursaturée en sucres dérivés du nectar recueilli et modifié par labeille, Apis mellifera . Le miel est utilisé depuis l'antiquité comme remède pour le traitement des plaies. Les preuves issues d'études animales et certains essais ont suggéré que le miel pourrait accélérer la cicatrisation des plaies.

Objectifs

L'objectif était de déterminer si le miel accélérait la vitesse de cicatrisation des plaies aiguës (par ex. les brûlures, les lacérations) et des plaies chroniques (par ex. les ulcères cutanés, les plaies chirurgicales infectées).

Stratégie de recherche documentaire

Pour cette première mise à jour de la revue, nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur les plaies et contusions (recherche effectuée le 13 juin 2012) ; le registre Cochrane des essais contrôlés (CENTRAL) ( The Cochrane Library 2012, numéro 5) ; Ovid MEDLINE (de 2008 à la 5ème semaine de mai 2012) ; Ovid MEDLINE (In-Process & Other Non-Indexed Citations 12 juin 2012) ; Ovid EMBASE (de 2008 à la semaine de 2012, 23) ; et EBSCO CINAHL (de 2008 au 8 juin 2012).

Critères de sélection

Des essais randomisés et quasi-randomisés évaluant le miel comme traitement pour tous types de plaies aiguës ou chroniques ont été recherchés. Il n'y avait aucune restriction en termes de source, de date de publication ou de langue. Le critère principal était la cicatrisation des plaies.

Recueil et analyse des données

Les données issues des essais éligibles ont été extraites et résumées par un auteur de la revue à l'aide d'un formulaire d'extraction de données et vérifiées de manière indépendante par un second auteur de la revue.

Résultats principaux

Nous avons identifié 25 essais (portant sur un total de 2987 participants) qui répondaient aux critères d'inclusion, dont six nouveaux essais qui ont été ajoutés à cette mise à jour. Pour les plaies aiguës, trois essais évaluaient l'effet du miel dans les lacérations aiguës, les abrasions ou les plaies chirurgicales mineures et 12 essais évaluaient l'effet du miel sur les brûlures. Pour les plaies chroniques, deux essais évaluaient l'effet du miel dans les ulcères veineux de jambe, et des essais uniques étudiaient son effet sur les plaies postopératoires infectées, les lésions de pression, de la leishmaniose cutanée, les ulcères du pied diabétique et la gangrène de Fournier. Trois essais ont recruté des personnes dans des groupes mixtes de plaies chroniques ou aiguës. La plupart des essais étaient à risque élevé ou incertain de biais. Pour les plaies aiguës, en particulier des brûlures du second degré, le miel pourrait réduire le temps de cicatrisation par rapport à des pansements conventionnels (DMP -4,68 jours, IC à 95 % -4,28 à -5,09 jours), mais, comparé à une excision précoce et à une greffe, le miel retarde la cicatrisation des brûlures aux deuxièmes et troisièmes degrés (DMP 13,6 jours, IC à 95 % 10,02 à 17,18 jours). Pour les plaies chroniques, le miel naugmente pas significativement la cicatrisation des ulcères veineux de jambe lorsqu'il est utilisé comme adjuvant à la compression (RR 1,15, IC à 95 % 0,96 à 1,38), et pourrait retarder la cicatrisation de la leishmaniose cutanée lorsqu'il est utilisé comme adjuvant à antimoniate de méglumine par rapport à lantimoniate de méglumine seule (RR de 0,72, IC à 95 % 0,51 à 1,01).

Conclusions des auteurs

Les pansements au miel ne sont pas augmenter les taux de cicatrisation de façon significative dans les ulcères veineux de jambe lorsqu'il est utilisé comme adjuvant à la compression. Le miel pourrait retarder la cicatrisation des brûlures aux deuxièmes et troisièmes degrés par rapport à une excision et à une greffe précoces, et dans la leishmaniose cutanée lorsqu'il est utilisé comme adjuvant à lantimoniate de méglumine. Le miel pourrait être plus efficace que certains matériaux de pansements conventionnels, mais il existe une incertitude considérable sur la reproductibilité et l'applicabilité de ces preuves. Il n'existe pas suffisamment de preuves pour orienter la pratique clinique dans d'autres types de plaies, et des services de santé peuvent prendre en compte en évitant l'utilisation systématique de pansements au miel tant que des preuves d'effet suffisantes soient disponibles.

Plain language summary

Honey as a topical treatment for acute and chronic wounds

Honey has been used on wounds since ancient times. Clinical trials have tested the effect of honey in both acute wounds (e.g. burns, lacerations) and chronic wounds (e.g. skin ulcers). The trials results show that honey might shorten healing times for moderate burns compared with some conventional dressings, but there is some serious doubt about the reliability of this finding. Honey used alongside compression therapy does not improve healing of venous leg ulcers. Honey may delay healing in deep burns and in ulcers caused by insect bites (cutaneous Leishmaniasis). There is not enough evidence to give guidance for the use of honey in other types of wounds.

Résumé simplifié

Le miel comme traitement topique des plaies aiguës et chroniques

Le miel est utilisé pour les plaies depuis l'antiquité. Des essais cliniques ont testé l'effet du miel dans les plaies aiguës (par ex. les brûlures, les lacérations) et les plaies chroniques (par ex. les ulcères cutanés). Les résultats des essais montrent que le miel pourrait raccourcir le temps de cicatrisation pour les brûlures modérées comparé à des pansements conventionnels, mais il existe de sérieux doutes quant à la fiabilité de ce résultat. Le miel utilisé en association avec la thérapie de compression n'améliore pas la cicatrisation des ulcères veineux de jambe. Le miel pourrait retarder la cicatrisation des brûlures profondes et des ulcères provoqués par des piqûres d'insectes (leishmaniose cutanée). Il n'existe pas suffisamment de preuves pour donner des recommandations en faveur de l'utilisation du miel dans d'autres types de plaies.

Notes de traduction

Traduit par: French Cochrane Centre 4th February, 2014
Traduction financée par: Pour la France : Ministère de la Santé. Pour le Canada : Instituts de recherche en santé du Canada, ministère de la Santé du Québec, Fonds de recherche de Québec-Santé et Institut national d'excellence en santé et en services sociaux.

Laički sažetak

Med kao lokalni pripravak za liječenje akutnih i kroničnih rana

Med se od davnina koristi za liječenje rana. Klinička su istraživanja provjeravala učinke meda na akutnim (npr. opekline, razderotine) i kroničnim (npr. kožni ulkusi) ranama. Rezultati tih istraživanja pokazuju da med može smanjiti vrijeme potrebno za oporavak umjerenih opekotina u usporedbi s nekim konvencionalnim zavojima, ali postoje ozbiljne sumnje u pouzdanost tih nalaza. Kad se koristi zajedno s kompresijskom terapijom med ne poboljšava liječenje venskih ulkusa na nogama. Med može odgoditi cijeljenje dubokih opekotina i ulkusa uzrokovanih ugrizima kukaca (kožna lišmenijaza). Zaključak je Cochrane sustavnog pregleda literature da nema dovoljno dokaza da bi se pružile smjernice o uporabi meda u ostalim vrstama rana.

Bilješke prijevoda

Cochrane Hrvatska
Preveo: Marin Viđak
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Background

Description of the condition

Acute and chronic wounds are terms in regular use in clinical practice, yet definition of these terms has received little attention. Lazarus 1994 suggested acute wounds proceed through to healing "in an orderly and timely reparative process". Orderliness refers to the healing sequence of inflammation, angiogenesis, matrix deposition, wound contraction, epithelialisation, and scar remodeling. Timeliness is subjective, but refers to a healing time that could be reasonably expected. A chronic wound is, therefore, a wound where the orderly biological progression to healing has been disrupted and healing is delayed.

Description of the intervention

Honey is a viscous, supersaturated sugar solution derived from nectar gathered and modified by the honeybee, Apis mellifera. Honey contains approximately 30% glucose, 40% fructose, 5% sucrose, and 20% water, as well as many other substances, such as amino acids, vitamins, minerals and enzymes (Sato 2000). Honey has been used in wound care since ancient times and is frequently mentioned in early pharmacopeia, although more usually as an ingredient or carrier vehicle rather than a specific treatment. Dioscorides (40-80 CE) often mentioned honey as a vehicle for carrying therapeutic agents in de materia medicis (Riddle 1985), and Hippocrates (460-377 BCE), who is often cited as advocating honey for wound care, simply listed it as one of many ingredients in a multitude of unguents (Adams 1939). Probably the first deliberate advocacy of honey as a wound treatment was by the anonymous author of the Edwin Smith papyrus, an Egyptian surgical text written between 2600-2200 BCE (Breasted 1930). A dressing made from honey and plant material was also recommended for treating burns in the London Medical Papyrus written around 1325 BCE (Trevisanato 2006). Other early medical customs, including Ayurvedic (Johnson 1992), Chinese (Fu 2001) and Roman traditions (Hajar 2002), also used honey in wound care.

How the intervention might work

From 1996 to 2006 there was a surge in interest about honey as a wound treatment, with 40 case reports or series in 875 patients published (Jull 2008). Recent research has tended to concentrate on the antibacterial activity of the many different types of honey, rather than its effect on wound healing (Molan 1999). Manuka honey, a monofloral honey derived from the Leptospermum tree in New Zealand and Australia, has been of particular interest, as it has antibacterial activity independent of the effect of honey's peroxide activity and osmolarity (Molan 2001). The substance (or substances) responsible for this non-peroxide activity has not been definitively identified, but has been termed Unique Manuka Factor (UMF). Manuka honey with a UMF rating has an antibacterial activity equivalent to a similar percentage of phenolic acid in solution. Recent research suggests methylglyoxal is the substance responsible for the non-peroxide activity (Mavric 2008).

There is evidence from different animal models that honey may accelerate healing (Bergman 1983; Oryan 1998; Postmes 1997). Fifteen of the 16 controlled trials in five different animal models (mice, rat, rabbit, pig, and buffalo calf) found that honey-treated incisional and excisional wounds, and standard burns, healed faster than control wounds (Jull 2008). In addition, a systematic review of honey as a wound dressing found seven randomised trials in humans, six in burns patients and one in infected post-operative wounds (Moore 2001). Although the poor quality of the trial reports prevented any recommendations, the findings did suggest an effect in favour of honey.

Honey may exert multiple microscopic actions on wounds. It appears to draw fluid from the underlying circulation, providing both a moist environment and topical nutrition that may enhance tissue growth (Molan 1999). Histologically, honey appears to stimulate tissue growth in animal and human controlled trials, with earlier tissue repair noted (Bergman 1983; Subrahmanyam 1998), fewer inflammatory changes (Oryan 1998; Postmes 1997), and improved epithelialisation (Oryan 1998). Macroscopically, reports have also noted the debriding action of honey (Blomfield 1973; Efem 1988; Ndayisaba 1993; Subrahmanyam 1991).

Why it is important to do this review

Communication with the authors of the earlier systematic review, Moore 2001, revealed that the authors had no plans to update the review (personal communication: RA Moore), and that other trials had been completed since the review was published. Therefore, an updated summary of the effect of honey on wound healing is warranted.

Objectives

The aim of this review is to assess whether the use of honey confers any benefit in wound healing. The objectives are to determine whether honey:

  • increases the rate of healing in acute wounds (e.g. burns, lacerations and other traumatic wounds);

  • increases the rate of healing in chronic wounds (e.g. venous ulcers, infected surgical wounds).

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) and quasi-randomised controlled trials were included. Quasi-randomised controlled trials are those trials that use a quasi-random allocation strategy, such as alternate days, date of birth, or hospital number.

Types of participants

Trials involving participants of any age with an acute or chronic wound were included. For the purposes of this review an acute wound was considered to be any of the following: burns, lacerations or other skin injuries resulting from minor trauma, and minor surgical wounds healing by primary or secondary intention. Chronic wounds were considered to be: skin ulcers of any type, pressure ulcers and infected wounds healing by secondary intention.

Types of interventions

The primary intervention was any honey topically applied by any means, alone or in combination with other dressings or components, to an acute or chronic wound. Comparison interventions were dressings or other topical agents applied to the wound.

Types of outcome measures

Trials had to provide data on one of the primary outcomes listed below, and the unit of analysis had to be by participant (See "Differences between protocol and review" for further information about unit of analysis issues).

Primary outcomes
  • Time to complete wound healing;

  • proportion of participants with completely healed wounds.

Secondary outcomes
  • Incidence of adverse events;

  • length of hospital stay;

  • change in wound size:

  • incidence of infection;

  • cost;

  • quality of life.

Search methods for identification of studies

Electronic searches

For the search methods used in the original version of this review see Appendix 1.

For this first update we searched the following databases for reports of eligible randomized controlled trials: 

  • Cochrane Wounds Group Specialised Register (searched 13 June 2012);

  • The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5);

  • Ovid MEDLINE (2008 to May Week 5 2012);

  • Ovid MEDLINE (In-Process & Other Non-Indexed Citations 12 June 2012);

  • Ovid EMBASE (2008 to 2012 Week 23);

  • EBSCO CINAHL (2008 to 8 June 2012)

The following search strategy was used in CENTRAL and adapted appropriately for other databases: 

#1 MeSH descriptor Skin Ulcer explode all trees
#2 MeSH descriptor Pilonidal Sinus explode all trees
#3 MeSH descriptor Wounds, Penetrating explode all trees
#4 MeSH descriptor Lacerations explode all trees
#5 MeSH descriptor Burns explode all trees
#6 MeSH descriptor Wound Infection explode all trees
#7 MeSH descriptor Surgical Wound Dehiscence explode all trees
#8 MeSH descriptor Bites and Stings explode all trees
#9 MeSH descriptor Cicatrix explode all trees
#10 ((plantar or diabetic or heel* or foot or feet or ischaemic or ischemic or venous or varicose or stasis or arterial or decubitus or pressure or skin or leg or mixed or tropical or rheumatoid or sickle
cell) NEAR/5 (wound* or ulcer*)):ti,ab,kw
#11 (bedsore* or (bed NEXT sore*)):ti,ab,kw
#12 (pilonidal sinus* or pilonidal cyst*):ti,ab,kw
#13 (cavity wound* or sinus wound*):ti,ab,kw
#14 (laceration* or gunshot stab or stabbing or stabbed or bite*):ti,ab,kw
#15 ("burn" or "burns" or "burned" or scald*):ti,ab,kw
#16 (surg* NEAR/5 infection*):ti,ab,kw
#17 (surg* NEAR/5 wound*):ti,ab,kw
#18 (wound* NEAR/5 infection*):ti,ab,kw
#19 (malignant wound* or experimental wound* or traumatic wound*):ti,ab,kw
#20 (infusion site* or donor site* or wound site* or surgical site*):ti,ab,kw
#21 (skin abscess* or skin abcess*):ti,ab,kw
#22 (hypertrophic scar* or keloid*):ti,ab,kw
#23 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR
#12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22)
#24 MeSH descriptor Honey explode all trees
#25 honey:ti,ab,kw
#26 (#24 OR #25)
#27 (#23 AND #26) 

The search strategies for Ovid MEDLINE, Ovid EMBASE and EBSCO CINAHL can be found in Appendix 2. We combined the Ovid MEDLINE search with the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity- and precision-maximizing version (2008 revision) (Lefebvre 2011). The Ovid EMBASE and EBSCO CINAHL searches were combined with the trial filters developed by the Scottish Intercollegiate Guidelines Network (SIGN) (SIGN 2008). There were no restrictions with respect to language, date of publication (taking into account searches from the original review) or study setting.

Searching other resources

For the initial review we contacted experts in the field, authors of the included trials and manufacturers of honey products for wound care (Comvita NZ Ltd and MediHoney Australia Pty Ltd), but did not repeat this for the update. The bibliographies of all obtained studies and review articles were searched for potentially eligible trials for both the initial review and this update. No language or date restrictions were applied to the trials and both published and unpublished trials were sought.

Data collection and analysis

Selection of studies

Two authors (AJ, NW) independently examined titles and abstracts of potentially relevant trials. Full text copies of all relevant trials, or trials that might be relevant to the review were obtained. The two review authors independently selected the trials using the inclusion criteria. Disagreements were resolved by discussion.

Data extraction and management

Data were extracted from included trials by one review author and recorded on a standardised form (AJ for the first review, SD for this update). The extracted data were independently reviewed for accuracy by a second review author (NW for the first review, AJ for this update) and disagreements resolved by discussion. If the data from the trial report were inadequate, or ambiguous, additional information was sought from the trial authors. We collected data on the topics listed below:

  1. Author; title; source of reference.

  2. Study setting.

  3. Study design.

  4. A priori sample size calculation; sample size.

  5. Inclusion/exclusion criteria.

  6. Age of participants; sex of participants.

  7. Wound type.

  8. Intervention and comparison.

  9. Outcomes.

  10. Withdrawals and reason for withdrawal.

  11. Funding source.

  12. Co-interventions.

Assessment of risk of bias in included studies

For this review update one review author (SD) assessed each included study using the Cochrane Collaboration tool for assessing risk of bias (Higgins 2011), and this assessment was checked by a second review author (AJ). This tool addresses six specific domains, namely sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other issues, such as extreme baseline imbalance (see Appendix 3 for details of criteria on which the judgement was based). Blinding and completeness of outcome data were assessed for each outcome separately. We completed a risk of bias table for each eligible study and discussed any disagreement amongst all review authors to achieve a consensus.

We presented an assessment of risk of bias using a 'risk of bias summary figure', which presents all of the judgements in a cross-tabulation of study by entry. This display of internal validity indicates the weight the reader may give the results of each study.

Data synthesis

Where trials were sufficiently alike in terms of population and comparison interventions, their results were combined. Mean differences (MD) and 95% confidence intervals (95% CI) were reported for continuous outcomes, and relative risk (RR) and 95% confidence intervals (95% CI) were reported for dichotomous variables. Statistical heterogeneity was tested by comparing Cochran's Q statistic and the chi-squared distribution. Heterogeneity was assumed with P values of less than 0.1 (Higgins 2011). In addition, the I2 statistic was used to determine the percentage of variation due to heterogeneity rather than chance (Higgins 2003), and any sources of heterogeneity were explored. Where significant statistical heterogeneity was present, a random-effects model was used when combining trials (Ioannidis 2008).

Results

Description of studies

Included studies

Twenty-five trials met the inclusion criteria (please see the Characteristics of included studies) and were available for analysis; six trials have been added since the first review (Baghel 2009; Mashood 2006; Memon 2005; Nilforoushzadeh 2007; Robson 2009; Shukrimi 2008), including one trial that was mistakenly excluded in the previous review, but was found to meet the inclusion criteria on re screening (Mashood 2006). One trial is awaiting assessment while attempts are made to contact the authors to request further data (Maghsoudi 2011).

Eleven trials were conducted by the same investigator (Subrahmanyam 1991; Subrahmanyam 1993a; Subrahmanyam 1993b; Subrahmanyam 1994; Subrahmanyam 1996a; Subrahmanyam 1996b; Subrahmanyam 1996c; Subrahmanyam 1998; Subrahmanyam 1999; Subrahmanyam 2001a; Subrahmanyam 2004).

Fifteen trials recruited participants with acute wounds - 12 with burns (Baghel 2009; Mashood 2006; Memon 2005; Subrahmanyam 1991; Subrahmanyam 1993b; Subrahmanyam 1994; Subrahmanyam 1996a; Subrahmanyam 1996b; Subrahmanyam 1996c; Subrahmanyam 1998; Subrahmanyam 1999; Subrahmanyam 2001a), two with minor surgical excisions (Marshall 2005; McIntosh 2006), and one with minor trauma (Ingle 2006). Eight trials recruited participants with chronic wounds including venous leg ulcers (Jull 2008; Gethin 2009), infected surgical wounds (Al Waili 1999), pressure injuries (Weheida 1991), Fournier's gangrene (Subrahmanyam 2004), cutaneous Leishmaniasis (ulcers caused by protozoans injected by sandfly bite) (Nilforoushzadeh 2007), diabetic foot ulcers (Shukrimi 2008), and mixed chronic wounds healing by secondary intention (Robson 2009). Two trials recruited participants with either a chronic or acute wound (Mphande 2007; Subrahmanyam 1993a).

Six trials were conducted in community settings or outpatient clinics (Gethin 2009; Ingle 2006; Jull 2008; Marshall 2005; McIntosh 2006; Nilforoushzadeh 2007). The remaining trials were conducted in hospital settings, or a mixed inpatient and outpatient setting (Robson 2009). Six trials reported recruiting only adults (Al Waili 1999; Gethin 2009; Ingle 2006; Jull 2008; Shukrimi 2008; Subrahmanyam 2004). The remaining trials did not specify an age range (Marshall 2005; McIntosh 2006; Robson 2009), or recruited both children and adults. Monofloral honey (aloe, jarrah, jamun, jambhul or manuka) was used in eight trials (Gethin 2009; Ingle 2006; Jull 2008; Marshall 2005; McIntosh 2006; Robson 2009; Subrahmanyam 2001a; Subrahmanyam 2004); the type of honey used was not specified in the remaining trials.

Five trials reported an a priori sample size calculation (Gethin 2009; Ingle 2006; Jull 2008; McIntosh 2006; Robson 2009). In one of these trials, the difference the study was powered to detect was not reported, although the effect was stated to be "clinically significant" (McIntosh 2006).

Excluded studies

For details on the excluded studies please see Characteristics of excluded studies table. Of the 46 excluded studies, 21 were not RCTs or quasi-RCTs (Abdelatif 2008; Ahmed 2003; Al Waili 2004c; Al Waili 2005; Bose 1982; Dunford 2004; Freeman 2010; Gethin 2005; Lusby 2002; Marshall 2002; Misirligou 2003; Molan 2002; Molan 2006; Mwipatayi 2004; Nagane 2004; Robson 2002; Schumacher 2004; Subrahmanyam 1993; Thurnheer 1983; Tostes 1994; Visscher 1996). Six of the excluded studies were not in wounds (Al Waili 2003; Albietz 2006; Biswal 2003; Johnson 2005; Quadri 1998; Quadri 1999). Three were studies in animal models (Al Waili 2004a; Al Waili 2004b; Subrahmanyam 2001b). Nine studies did not report sufficient information on healing (Bangroo 2005; Chokotho 2005; Gad 1988; Jeffery 2008; Lund-Nielsen 2011; Oluwatosin 2000; Rogers 2010; Rucigaj 2006; Subrahmanyam 2003). Two studies were not in honey (Berchtold 1992; Muller 1985) and a further two could not be obtained for assessment (Calderon Espina 1989; Rivero Varona 1999). Three studies had unit of analysis issues, they had randomised, or reported, by wound rather than by the participant. Such unit of randomisation or analysis issues were not considered in the protocol for the review, but we considered that such studies could not contribute usefully to this review. For further discussion on the rationale for this decision see "Differences between protocol and review" (Malik 2010; Okeniyi 2005; Yapucu Gunes 2007).

Risk of bias in included studies

Overall the trials were mostly at high or unclear risk of bias (Figure 1; Figure 2).

Figure 1.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Sequence generation

One trial used a pseudo-randomised strategy of alternating admissions and was judged to be at high risk of bias (Mphande 2007). Twenty-four trials were described as randomised controlled trials, but only eight reported how their allocation sequence had been generated (Gethin 2007; Ingle 2006; Jull 2008; Marshall 2005; McIntosh 2006; Mphande 2007; Nilforoushzadeh 2007; Robson 2009). One author supplied additional information that enabled us to judge the method of sequence generation for this study as adequate (personal communication: G Gethin). The remaining six trials reported the method of sequence generation adequately, and thus seven trials were judged to be at low risk of bias. Another author also supplied additional information on 11 trials, where the method for allocation sequence was described as the "chit method" (personal communication: M Subrahmanyam) (Subrahmanyam 1991; Subrahmanyam 1993a; Subrahmanyam 1993b; Subrahmanyam 1994; Subrahmanyam 1996a; Subrahmanyam 1996b; Subrahmanyam 1996c; Subrahmanyam 1998; Subrahmanyam 1999; Subrahmanyam 2001a; Subrahmanyam 2004), however, it is not known what this method involved, and, therefore, the risk of bias was judged to be unclear for these 11 trials as well as the remaining six trials for which no further information was available (Al Waili 1999; Baghel 2009; Mashood 2006; Memon 2005; Shukrimi 2008; Weheida 1991).

Allocation concealment

Allocation concealment was reported in five trials, and was judged to be adequate and, therefore, at low risk of bias for this domain (Gethin 2009; Jull 2008; Marshall 2005; McIntosh 2006; Robson 2009). All these trials achieved allocation concealment by using an independent central telephone system. One trial allocation was judged as inadequately concealed as the admissions were done on alternation basis (Mphande 2007), and was, therefore, at high risk of bias for this domain. Additional information was supplied for 11 trials, where the method of allocation concealment was described as "sequential numbered envelopes" or "sequential numbered envelopes, which are sealed" (personal communication: M Subrahmanyam) (Subrahmanyam 1991; Subrahmanyam 1993a; Subrahmanyam 1993b; Subrahmanyam 1994; Subrahmanyam 1996a; Subrahmanyam 1996b; Subrahmanyam 1996c; Subrahmanyam 1998; Subrahmanyam 1999; Subrahmanyam 2001a; Subrahmanyam 2004). It is not known whether the envelopes were opaque, therefore, these trials, and the remaining trials (Al Waili 1999; Baghel 2009; Ingle 2006; Memon 2005; Nilforoushzadeh 2007; Shukrimi 2008; Weheida 1991), were judged as having unclear risk of bias.

Blinding

Blinding: participants - all outcomes

Adequate blinding of participants was clearly reported in one trial (McIntosh 2006). Fifteen trials reported inadequate blinding of participants (Jull 2008; Gethin 2007; Marshall 2005; Robson 2009; Subrahmanyam 1991; Subrahmanyam 1993a; Subrahmanyam 1993b; Subrahmanyam 1994; Subrahmanyam 1996a; Subrahmanyam 1996b; Subrahmanyam 1996c; Subrahmanyam 1998; Subrahmanyam 1999; Subrahmanyam 2001a; Subrahmanyam 2004); of these three trials were open labelled trials (Jull 2008; Gethin 2007; Robson 2009), two trials reported the participants were not blinded (Marshall 2005; Subrahmanyam 2004), and 10 trials did not report blinding in the published report, but the author responded to a request for further information stating the patients were not blinded (Subrahmanyam 1991; Subrahmanyam 1993a; Subrahmanyam 1993b; Subrahmanyam 1994; Subrahmanyam 1996a; Subrahmanyam 1996b; Subrahmanyam 1996c; Subrahmanyam 1998; Subrahmanyam 1999; Subrahmanyam 2001a). The remaining 9 trials, including one that claimed to be a double blind study (Ingle 2006), either provided insufficient information to permit a judgement on blinding of participants, or did not report on blinding (Al Waili 1999; Baghel 2009; Ingle 2006; Mashood 2006; Memon 2005; Mphande 2007; Nilforoushzadeh 2007; Shukrimi 2008; Weheida 1991), therefore, these trials were judged as having an unclear risk of bias

Blinding: healthcare providers - all outcomes

The blinding of healthcare providers was judged to be inadequate in six trials (Gethin 2007; Jull 2008; Marshall 2005; McIntosh 2006; Robson 2009; Subrahmanyam 2004). Three of the six trials were open labelled (Jull 2008; Gethin 2007; Robson 2009). Two of the six trials were single blinded - as clinicians were not blinded (Marshall 2005; Subrahmanyam 2004) - and the third trial was double blinded, with participants and outcome assessors blinded, but health care providers not blinded (McIntosh 2006). The remaining 19 trials were judged as having an unclear risk of bias. Information was supplied by one author on 10 trials, who stated that the investigators were blinded to participant allocation (Subrahmanyam 1991; Subrahmanyam 1993a; Subrahmanyam 1993b; Subrahmanyam 1994; Subrahmanyam 1996a; Subrahmanyam 1996b; Subrahmanyam 1996c; Subrahmanyam 1998; Subrahmanyam 1999; Subrahmanyam 2001a), but the information provided was insufficient to permit a judgement on the risk of bias and therefore it was deemed to be unclear. One trial was reported as double-blind (Ingle 2006), but there was insufficient information about blinding to permit a judgement on risk of bias. The remaining trials did not report on blinding (Al Waili 1999; Baghel 2009; Mashood 2006; Memon 2005; Mphande 2007; Nilforoushzadeh 2007; Shukrimi 2008; Weheida 1991).

Blinding: outcome assessors - all outcomes

Adequate blinding of participants was clearly reported in six trials (Ingle 2006; McIntosh 2006; Marshall 2005; Nilforoushzadeh 2007; Shukrimi 2008; Subrahmanyam 2004). The blinding of outcome assessors was judged to be inadequate in three trials that were open-labelled (Gethin 2007; Jull 2008; Robson 2009), although one used blinded review of photographs in a sensitivity analysis for the primary outcome (Jull 2008). The remaining 16 trials Information were judged as having an unclear risk of bias; although information about 10 trials was supplied by one author who stated that the outcome assessors were blinded to participant allocation the review authors judged there was insufficient information to permit a judgement on blinding of participants (Subrahmanyam 1991; Subrahmanyam 1993a; Subrahmanyam 1993b; Subrahmanyam 1994; Subrahmanyam 1996a; Subrahmanyam 1996b; Subrahmanyam 1996c; Subrahmanyam 1998; Subrahmanyam 1999; Subrahmanyam 2001a). The remaining 6 trials, either provided insufficient information to permit a judgement on blinding of participants or did not report on blinding (Al Waili 1999; Baghel 2009; Mashood 2006; Memon 2005; Mphande 2007; Weheida 1991).

Incomplete outcome data

Incomplete outcome data addressed: drop-out rate described and acceptable - all outcomes

The drop-out rate was described adequately and was acceptable in 19 trials and these trials were judged as having low risk of bias for this domain. Thirteeen trials did not have any missing data (Al Waili 1999; Baghel 2009; Mashood 2006; Memon 2005; Subrahmanyam 1991; Subrahmanyam 1993a; Subrahmanyam 1993b; Subrahmanyam 1994; Subrahmanyam 1996a; Subrahmanyam 1996b ; Subrahmanyam 1996c; Subrahmanyam 1998; Subrahmanyam 2001a), and six trials reported a drop-out rate that was below 10% (Gethin 2007; Ingle 2006; Jull 2008; Robson 2009; Subrahmanyam 1999; Subrahmanyam 2004). The drop-out rate was greater than 10% in three trials (Marshall 2005; McIntosh 2006; Nilforoushzadeh 2007), which were judged as being at high risk of bias. The remaining three trials provided insufficient information to permit a judgement to be made on drop-out rates (Mphande 2007; Shukrimi 2008; Weheida 1991), and these trials were judged as having an unclear risk of bias.

Incomplete outcome data addressed: intention-to-treat (ITT) analysis - all outcomes

In 13 trials there were no drop-outs reported, with all the randomised patients included in the final analysis, and hence the trials were judged as having a low risk of bias (Al Waili 1999; Baghel 2009; Mashood 2006; Memon 2005; Subrahmanyam 1991; Subrahmanyam 1993a ; Subrahmanyam 1993b; Subrahmanyam 1994; Subrahmanyam 1996a; Subrahmanyam 1996b; Subrahmanyam 1996c; Subrahmanyam 1998; Subrahmanyam 2001a). Furthermore, three trials reported using intention-to-treat (ITT) analysis (Gethin 2009; Jull 2008; Robson 2009), and were also judged as having a low risk of bias. Four trials did not undertake ITT analysis and randomised participants were not all included in the final analysis (Ingle 2006; Marshall 2005; McIntosh 2006; Nilforoushzadeh 2007). Therefore, these trials were judged as having a high risk of bias . In the remaining five trials, it was not known whether ITT analysis was used, and these trials were judged as having an unclear risk of bias (Mphande 2007; Shukrimi 2008; Subrahmanyam 1999; Subrahmanyam 2004; Weheida 1991).

Selective reporting

This domain was judged to be at low risk of bias in all trials. Though the study protocols were not available, the important outcome measures stated in the methods section were reported in the results in all trials.

Other potential sources of bias

Twelve trials were judged as having a low risk of bias because there was no imbalance in the baseline characteristics and the studies appeared to be free from other forms of bias (Al Waili 1999; Baghel 2009; Gethin 2009; Ingle 2006; Jull 2008; Robson 2009; Subrahmanyam 1991; Subrahmanyam 1994; Subrahmanyam 1996b; Subrahmanyam 1996c; Subrahmanyam 1998; Subrahmanyam 2001a). Four studies were judged as having a high risk of bias because there was baseline imbalance (McIntosh 2006; Marshall 2005; Memon 2005; Weheida 1991). The remaining nine trials provided insufficient information to enable a judgement on other potential source of biases, and these trials were judged as having unclear risk of bias (Mashood 2006; Mphande 2007; Nilforoushzadeh 2007; Shukrimi 2008; Subrahmanyam 1993a; Subrahmanyam 1993b; Subrahmanyam 1996a; Subrahmanyam 1999; Subrahmanyam 2004).

Effects of interventions

The 25 trials included 2987 participants. The trials were generally small (median size 87, range 30 to 900), and there was very obvious clinical and methodological heterogeneity. It was not appropriate, therefore, to combine the trials in a single meta-analysis to produce a summary statistic for honey overall, or even subgroup summary statistics for acute, chronic, or mixed wounds. Within the subgroups (acute, mixed acute and chronic, and chronic wounds) trials have been combined in meta-analysis where appropriate. Otherwise the trials have been summarised narratively.

1. Acute wounds

1.1 Minor acute wounds

Three trials (213 participants) recruited participants with minor acute wounds (Ingle 2006; Marshall 2005; McIntosh 2006). In two trials, the wounds were surgical wounds created after partial or total toenail avulsions (Marshall 2005; McIntosh 2006), with the control group treated with paraffin gauze in one trial and an iodophor dressing in the other. The remaining trial recruited mine workers with lacerations or shallow abrasions and treated control participants with a hydrogel (Ingle 2006). We combined trial findings using a fixed-effect model. There was no statistically significant difference between treatments for mean days to healing (WMD 1.55 days, 95% CI -1.91 to 5.00 days Analysis 1.1). Moderate heterogeneity was present (I2 = 48%).

1.2 Burns

There were six comparison treatments, which have been grouped under the four broad categories of conventional dressings, early excision, silver sulfadiazine (SSD) and unconventional dressings for this review. Three new trials have been added to the honey versus SSD comparison in this update of the review (Baghel 2009; Mashood 2006; Memon 2005).

1.2.1 Honey compared with conventional dressings

Two trials (992 participants) compared honey with conventional dressings for the treatment of partial-thickness burns (Subrahmanyam 1993a; Subrahmanyam 1996a). In one trial (Subrahmanyam 1993a) the comparison was a polyurethane film dressing and in the other trial (Subrahmanyam 1996a) the control participants were treated with either a polyurethane film (OpSite, n = 90), Vaseline-impregnated gauze (n = 90), sterile linen dressings (n = 90), a Soframycin dressing (n = 90) or left exposed (n = 90). Mean days to healing were reported, but not the standard deviations, though this information was provided by the author (personal communication: M Subrahmanyam). Mean time to healing significantly favoured honey (WMD -4.68 days, 95% CI -4.28 to -5.09 days, Analysis 2.1).

1.2.2 Honey compared with early excision and grafting

One trial (50 participants) compared early tangential excision and skin grafting with honey dressings and delayed excision and skin grafting for the treatment of mixed partial- and full-thickness burns (Subrahmanyam 1999). Mean time to healing was not published, but was provided by the author (personal communication: M Subrahmanyam). Mean time to healing significantly favoured early excision and grafting (WMD -13.6 days, 95% CI -10.02 to -17.18 days, Analysis 3.1).

1.2.3 Honey compared with silver sulfadiazine

Six trials (462 participants) compared honey with silver sulfadiazine (Baghel 2009; Mashood 2006; Memon 2005; Subrahmanyam 1991; Subrahmanyam 1998; Subrahmanyam 2001a). The trials used a mixture of burn grading systems to report the depth of burns, which reflected the age of the trials and the lack of a clinical consensus on reporting burn depth. The burns, however, did tend towards the less severe end of the spectrum, although early staging systems (e.g. first-, second- and third-degree burns, or superficial, partial-thickness and full-thickness) do not have the sensitivity of more recent systems (i.e. epidermal, superficial dermal, mid-dermal, deep dermal and full-thickness), and participants with deep partial-thickness and deep dermal burns are likely to require skin grafting (NZGG 2007).

Trials recruited participants with first- and second-degree burns (Baghel 2009), superficial burns (Subrahmanyam 1991; Subrahmanyam 1998), superficial partial- and deep partial-thickness burns (Mashood 2006), and one recruited participants with superficial, dermal, mid and deep dermal burns (Memon 2005). The remaining trial did not report on the depth of the burns in participants (Subrahmanyam 2001a). One trial reported mean time to healing and time to healing data (Subrahmanyam 2001a), and five trials reported either mean time to healing without standard deviations (Baghel 2009; Memon 2005), or time to complete healing (Mashood 2006; Subrahmanyam 1991; Subrahmanyam 1998), but on different schedules for reporting e.g. healing at two, four, and six weeks in one trial (Mashood 2006), and at days seven and 21 in another (Subrahmanyam 1998). Additional information was sought from authors and provided by one author (personal communication: M Subrahmanyam). Thus mean time to healing was used as the outcome, with the result that only three trials could be incorporated into a meta-analysis.

The mean time to healing was not significantly different (WMD -4.37 days, 95% CI -8.94 to 0.19, Analysis 4.1). A random-effects model was used as there was significant statistical heterogeneity (P < 0.00001, I2 = 95%) despite the apparent clinical and methodological similarities. Statistical heterogeneity appears to have been contributed by one trial (Subrahmanyam 1991), but it was not possible to determine what it was about this trial that caused the heterogeneity. In the two trials that did not report standard deviations with mean time to healing (Baghel 2009; Memon 2005), one trial reported that for the honey-treated group mean time to healing was 15.3 days and 20.0 days in the SDD group (Baghel 2009), while the other trial reported it as 18.16 days in the honey group and 31.68 days in the SSD-treated group (Memon 2005). In the remaining trial (Mashood 2006), all 25 patients in the honey-treated group were healed by four weeks, while all patients in the SDD group were healed by six weeks.

1.2.4 Honey compared with unconventional dressings

Three trials (248 participants) by the same investigator compared honey with unconventional dressings or materials (Subrahmanyam 1994; Subrahmanyam 1996b; Subrahmanyam 1996c). The interventions were too dissimilar to combine in a meta-analysis. Therefore the trials are summarised here in a narrative review.

One trial (100 participants) recruited participants with partial-thickness burns and compared honey to treatment with boiled potato-peel dressings (Subrahmanyam 1996b). Mean days to healing was reported without standard deviations. This information was supplied by the author (personal communication: M Subrahmanyam). The findings clearly favoured the honey. Mean time to healing favoured honey (MD -5.8 days, 95% CI -4.92 to -6.88 days) (Analysis 5.1).

The remaining two trials recruited participants with partial-thickness burns. One trial (64 participants) compared honey-impregnated gauze with treatment with amniotic membranes (Subrahmanyam 1994). Mean time to healing was reported without standard deviations, but this information was supplied by the author (personal communication: M Subrahmanyam). Mean time to healing was not significantly different between groups (MD 1.9 days, 95% CI -0.88 to 4.68 days, Analysis 5.1). The second trial (84 participants) compared honey to treatment with honey-plus (honey with added vitamins C and E, and polyethylene glycol) (Subrahmanyam 1996c). Mean time to healing was reported without standard deviations, but this information was supplied by the author (personal communication: M Subrahmanyam). Mean time to healing favoured the honey-plus group (MD 1.9 days, 95% CI 0.59 to 3.21 days) (Analysis 5.1).

2. Mixed acute and chronic wounds

Three trials (245 participants), including a new trial added in this update (Robson 2009), recruited participants with a mix of acute and chronic wounds (Mphande 2007; Robson 2009; Subrahmanyam 1993b).

Subrahmanyam 1993b (100 participants) recruited participants with burns, lower limb ulcers caused by trauma, pressure, diabetes, and venous disease, or trophic ulcers. The comparison treatment was SSD. Information on overall mean time to healing was provided by the author (personal communication: M Subrahmanyam). The mean time to healing favoured honey (MD -13.0 days, 95% CI -10.76 to -15.24) (Analysis 6.1).

Mphande 2007 (40 participants) recruited participants with ulcers, chronic osteomyelitis, abscesses, post-surgical or traumatic wounds; the comparison treatment was sugar dressings. Median time to complete healing was 31.5 days in the honey-treated group and 56.0 days in the sugar-treated group.

Robson 2009 (105 participants) recruited participants with any type of wound healing by secondary intention, including leg ulcers, foot ulcers, surgical wounds, donor site wounds, and pressure injuries, but EPUAP grade 1 and 4 pressure injuries were excluded. Participants were allocated to receive either manuka honey or a usual care dressing. If slough was present, control participants were to be treated in the first instance with a hydrogel. The healing rates at 12 weeks (46.2% versus 34.0%) and 24 weeks were not significantly different (72.7% versus 63.3%, RR 1.14, 95% CI 0.88 to 1.48) (Analysis 6.2).

3. Chronic Wounds

Seven trials (636 participants), including two trials added in this update (Nilforoushzadeh 2007; Shukrimi 2008), recruited participants with chronic wounds, including venous leg ulcers (Gethin 2009; Jull 2008), diabetic foot ulcers (Shukrimi 2008), ulcers caused by Leishmaniasis (Nilforoushzadeh 2007), pressure injuries (Weheida 1991), infected post-operative wounds (Al Waili 1999), and Fournier's gangrene (Subrahmanyam 2004). Three trials reported either mean time to healing (Al Waili 1999; Weheida 1991), or surgical closure (Shukrimi 2008). Three trials reported proportion of participants with completely healed ulcers (Gethin 2009; Jull 2008; Nilforoushzadeh 2007). Only mean hospital stay was reported in one trial, but data on mean time to healing were provided by the author (Subrahmanyam 2004). Given the clinical and methodological heterogeneity between the trials, it was not possible to combine the trials to produce a summary statistic.

3.1 Infected post-operative wounds

One trial (50 participants) randomly allocated participants with infected Caesarean or hysterectomy wounds to twice daily applications of honey or antiseptic washes of 70% ethanol and povidone-iodine (Al Waili 1999), in addition to systemic antibiotics. There was very limited information on baseline comparability and no indication of the duration of treatment or length of follow-up. Mean time to healing favoured the honey-treated group (MD -11.31 days, 95% CI -8.22 to -14.40) (Analysis 7.1).

3.2 Pressure injuries

One trial (40 participants) randomly allocated participants with uninfected grade I or grade II pressure injuries greater than 2 cm in diameter to daily applications of honey or saline-soaked gauze dressings (Weheida 1991). There was very limited information on baseline comparability and no indication of the duration of treatment or length of follow-up. Mean time to healing favoured the honey-treated group (MD -1.73 days, 95% CI -1.09 to -2.37, Analysis 7.1).

3.3 Fournier's gangrene

One trial (30 participants) of men with Fournier's gangrene randomly allocated participants to treatment with monofloral (jamun) honey-soaked gauze dressings or antiseptic EUSOL-soaked gauze dressings (Subrahmanyam 2004). Fournier's gangrene is an infection of the scrotum that can also involve the perineum and abdominal wall. One participant in the honey-treated group died, and two participants in the EUSOL group died. Skin grafting was required in nine participants in each group. Only mean length of hospital stay was reported in the paper, but mean time to healing was supplied by the author (personal communication M Subrahmanyam). Mean time to healing significantly favoured the honey-treated group (MD -8.00 days, 95% CI -6.08 to -9.92 days, Analysis 7.1).

3.4 Cutaneous Leishmaniasis

One trial (100 participants) randomly allocated participants with ulcers caused by Leishmaniasis to treatment with honey-soaked gauze dressings in addition to intralesional injections with meglumine antimoniate (glucantamine) or intralesional injections alone (Nilforoushzadeh 2007). The paper only reported on 45 participants per arm and it was not possible to determine the numbers unaccounted for in each arm. Thus the denominators could not be corrected in the meta-analysis. The proportion healed was lower in the honey plus intralesional injection group at four months (51.1% versus 71.1%) and the difference was not significant (RR 0.72, 95% CI 0.51 to 1.01) (Analysis 7.2).

3.5 Venous leg ulcers

Two trials recruited participants with venous leg ulcers. One trial (368 participants) recruited patients presenting to community-based nursing services for assessment and treatment of their venous ulcers (Jull 2008). Participants were allocated to receive either manuka honey-impregnated calcium alginate dressings or usual care. Participants allocated usual care could receive any dressing that was clinically indicated from the wide range normally available to community nurses (non-adherent, alginate, hydrogel, hydrofibre, hydrocolloid, silver or iodophor dressings). Both groups received compression bandaging as a standard background treatment. Participants were treated for 12 weeks. The second trial (108 participants) recruited participants with uninfected venous ulcers which were 50% or more covered with slough (Gethin 2009). Participants were allocated to receive either manuka honey dressings or hydrogel dressings for four weeks and then standard care for the remaining eight weeks of the 12 week follow-up. Both groups received compression bandaging as a standard background treatment. The primary outcome was change in area of slough at four weeks with healing reported at 12 weeks as a secondary outcome. Although the duration of treatment was dissimilar, they were considered sufficiently alike to be able to provide meaningful information when combined. The I2 was 0% and combination of the two trials found no significant effect of honey on ulcer healing at 12 weeks (RR 1.15, 95% CI 0.96 to 1.38, Analysis 7.2 )

3.6 Diabetic foot ulcers

One trial (30 participants) allocated participants with Wagner grade II diabetic foot ulcers to treatment with honey and gauze dressings or povidine-iodine and gauze dressings following surgical debridement and background treatment with antibiotics (Shukrimi 2008). Wagner grade II staging indicates that the ulcer involves ligament, tendon, joint capsule or fascia. The mean time to surgical closure was 14.4 days in the honey-treated group and 15.4 days in the povidine-iodine group. The study did not report standard deviations, but stated the difference was not statistically significant.

4. Adverse events

One trial did not report adverse events (Weheida 1991), and three trials reported that no adverse events occurred (Marshall 2005; McIntosh 2006; Subrahmanyam 1996b). One trial reported any adverse event (Jull 2008), whereas the remaining trials appear to have limited reporting of events to specific types of events, rather than encouraging reports of any event. Adverse events are presented by wound type and the findings have been combined using a random-effects model due to heterogeneity of results in the burns subgroup. Although only one trial explicitly reported frequency of events by participant (Jull 2008), it is assumed one event equals one participant in all other trials.

4.1 Minor acute wounds

Ingle and colleagues reported the frequency of itching, burning and pain (Ingle 2006). There was no significant difference between honey and hydrogel (RR 1.37, 95% CI 0.77 to 2.45) (Analysis 8.1).

4.2 Burns

Seven trials reported the frequency of hypergranulation, contracture, hypertrophic scarring or minor scarring as adverse events (Memon 2005; Subrahmanyam 1991; Subrahmanyam 1993a; Subrahmanyam 1994; Subrahmanyam 1996a; Subrahmanyam 1999; Subrahmanyam 2001a). There was no statistically significant difference between honey and the control treatments (RR 0.85, 95% CI 0.29 to 2.51) (Analysis 8.1). The frequency of the different adverse events is presented in Table 1.

Table 1. Frequency of adverse events reported in burns trials (Memon 2005; Subrahmanyam 1991, 1993a, 1994, 1996a, 1999, 2001a)
Adverse eventHoneyControl treatment
Hypergranulation8/54817/548
Contracture11/25321/237
Minor scarring28/45087/450
Hypertrophic scarring0/527/52
4.3 Infected post-operative wounds

One trial reported the frequency of wound dehiscence (Al Waili 1999). There was a statistically significant difference with fewer adverse events in the honey group (RR 0.31, 95% CI 0.11 to 0.82) (Analysis 8.1).

4.4 Fournier's gangrene

One trial reported the frequency of mortality (Subrahmanyam 2004). There was no significant difference in patient deaths between treatment groups (RR 0.57, 95% CI 0.06 to 5.65) (Analysis 8.1).

4.5 Venous leg ulcers

One trial reported all adverse events, whether or not the event was believed to be related to the treatment (Jull 2008), whereas the other trial reported events that were attributable to the wound agent, of which there were none (Gethin 2009). There were significantly more adverse event reported in the honey-treated group (RR 1.28, 95% CI 1.05 to 1.56) (Analysis 8.1). The frequency of the different adverse events in presented in Table 2.

Table 2. Frequency of adverse events reported in venous ulcer trial (Jull 2008)
Adverse eventHoney treatmentControl treatment
Ulcer pain47/18718/181
Bleeding3/1873/181
Dermatitis8/1878/181
Deterioration of ulcer19/1879/181
Erythema6/1874/181
Oedema4/1871/181
Increased exudate5/1871/181
Deterioration of surrounding skin5/1873/181
New ulceration16/18715/181
Other6/1873/181
Cardiovascular4/1873/181
Cancer2/1872/181
Neurological4/1871/181
Gastrointestinal4/1872/181
Injury10/1879/181
Musculoskeletal13/1879/181
Respiratory6/1873/181
Other3/1878/181
4.6 Wounds healing by secondary intention

One trial reported on mortality, pain, and ulcer deterioration (Robson 2009). Its is not clear whether the events were believed to be related to treatment or not. There was no significant difference between groups in adverse events (RR 2.04, 95% CI 0.39 to 10.65) (Analysis 8.1)

5. Incidence of infection

Three trials reported the incidence of infection ( Jull 2008; Marshall 2005; McIntosh 2006), and a fourth study reported withdrawals due to infection (Gethin 2009). Infection was operationally defined as clinical signs of infection or a positive swab result, and treatment with antibiotics in one trial (Jull 2008); in the other trials infection was described as clinically diagnosed and requiring referral for antibiotics. There was no significant difference in infection rates (RR 0.72, 95% CI 0.50 to 1.04) (Analysis 9.1).

Seven burns trials reported the proportion of patients with positive swab cultures at admission that were rendered sterile after seven days' treatment with honey compared with another non-honey treatment (Baghel 2009; Subrahmanyam 1991; Subrahmanyam 1993a; Subrahmanyam 1994; Subrahmanyam 1996b; Subrahmanyam 1998; Subrahmanyam 2001a). The relative risk of rendering a burn sterile after seven days treatment was in favour of honey (RR 5.31, 95% CI 1.75 to 16.18) (Analysis 9.2), but significant heterogeneity was present (P < 0.00001, I2 = 96%). All trials were of similar (low) quality, and removal of the trials that used treatments other than SSD as a comparison treatment did not reduce the heterogeneity (RR 13.67, 95% CI 0.29 to 642.49, P < 0.00001, I2 96%) (Subrahmanyam 1993b; Subrahmanyam 1994; Subrahmanyam 1996b). An eighth trial reported that time to sterility in patients treated with honey was three weeks compared to five weeks for SSD (Mashood 2006).

6. Cost

Three trials reported cost information (Ingle 2006; Jull 2008; Mashood 2006): these trials compared honey with hydrogel in participants with shallow wounds and abrasions (Ingle 2006); honey with usual care in venous leg ulceration (Jull 2008); and honey with SSD in patients with superficial- and partial-thickness burns (Mashood 2006). Only one of these analyses was a cost-effectiveness analysis (Jull 2008). Ingle 2006 and Mashood 2006 both reported that the honey cost less than the product with which it was compared.

Jull 2008 and colleagues conducted a full cost-effectiveness analysis using a health service perspective. Information was collected on dressings and related products, district nursing time, general practitioner and laboratory time, outpatient consultations, antibiotic use, and hospitalisation. In the base case analysis, the average cost of treatment with honey was NZD 917.00 per participant compared to NZD 972.68 per participant for usual care. This cost was driven by a small difference in hospitalisations that was considered likely to be due to chance variation (three participants in the honey group were hospitalised for ulcer-related reasons for 10 days, compared to six participants hospitalised for 40 days). A sensitivity analysis excluding the hospitalisations found the average cost of treatment was reversed with usual care being cheaper (NZD 811.12 per participant) than treatment with honey (NZD 877.90 per participant). Incremental cost-effectiveness ratios were calculated, but are not reported here, as effectiveness was not established, and, therefore, cost-effectiveness ratios could be misleading.

7. Quality of life

One trial of honey for treating venous leg ulcers reported data on health-related quality of life (Jull 2008). Two generic instruments (SF-36, EQ5D) and one disease-specific instrument (Charing Cross Venous Ulcer Questionnaire) were used. A small, but statistically significant, improvement in the physical functioning domain of SF-36 was found in favour of honey (mean difference 4.6, 95% CI 0.5 to 8.7), but no differences were found in any of the other domains measured by the SF-36. In addition, there was no significant difference between the groups for either physical summary component score (mean difference 1.1, 95% CI -0.8 to 3.0) or the mental component summary score (mean difference 0.7, 95% CI -1.1 to 2.4). There were also no significant differences on any domain measured by EQ5D or the Charing Cross Venous Ulcer Questionnaire.

Discussion

This is a complex review addressing a diverse range of wound types and many trials at high or unclear risk of bias. The findings are discussed below with respect to specific wound types.

1. Acute wounds

1.1 Minor acute wounds

The evidence currently does not support the use of honey in acute wounds such as abrasions and lacerations, or on minor uncomplicated wounds left to heal by secondary intention following surgery. Further trials of honey may be justified in these types of wounds, as the possibility of a modest effect in favour of honey cannot be ruled out.

1.2 Burns

The evidence with respect to the treatment of burns is mixed. Honey appears to delay healing compared with early excision and skin grafting in mixed-depth burns (i.e. both partial- and deep-thickness burns). These findings were derived from one small trial, but the effect was such that early excision and grafting must be considered the superior alternative.

Honey might be more effective than some dressings (impregnated gauze, saline soaks, or polyurethane film dressings) in partial-thickness burns. The trials lacked sufficient detail to determine risk of bias accurately for most domains, the comparators may not be applicable to burn healing in developed nations, and burn depth was described using an older taxonomy (partial-thickness burns), which has been superceded by more sensitive classification systems. It is not clear, therefore, for which burn depths the evidence is applicable, even if honey is superior to other conventional dressing materials.

The effect of honey compared with silver sulfadiazine (SSD) in treating burns has not been established, despite six trials. The lack of a uniform approach to trial design, assessment of burn depth, outcomes and follow-up periods meant the six trials could not be combined. The clinical and methodological heterogeneity suggests triallists are not considering prior evidence and the need to address gaps in the evidence when designing their trials. Such variability means the research itself is wasted effort. Overall the trials seem to point to an effect in favour of honey, but such an effect could be as a consequence of the SSD delaying healing rather than honey promoting healing. Previously, use of SSD until healing is achieved has been found to lengthen healing times in comparison to inactive treatments, such as hydrocolloid dressings and silicone-impregnated dressings (Wasiak 2006). It is in recognition of this evidence that guidelines recommend SSD only be used for limited periods in the treatment of`burns rather than for the entire treatment period (NZGG 2007).

The evidence for honey compared with other treatments in the treatment of burns is even more uncertain. While amniotic membrane dressings performed better than honey dressings in one trial, honey dressings performed better than boiled potato dressings in another trial. Both trials were small and of uncertain quality and thus these results should only be used to inform future research efforts.

2. Mixed acute and chronic wounds

The rationale for conducting trials in which the participants have either burns or a mix of chronic wounds is unclear. The aetiologies are so different that no matter whether the results are positive, negative or inconclusive, the findings are unlikely to influence clinical practice, as practitioners will struggle with application of the evidence. Further trials in such heterogenous populations are not justified.

3. Chronic wounds

The effect of honey in the treatment of chronic wounds, with the exception of venous leg ulcers and cutaneous Leishmaniasis, cannot be established based on current evidence. Most trials were small, with inappropriate comparators and at high or unclear risk of bias.

3.1 Infected post-operative wounds

The effect of honey as an adjuvant to systemic antibiotics in infected post-operative wounds cannot be determined. The trial was small, lacked sufficient detail to permit the risk of bias to be determined accurately for most domains, and the comparator was also an antiseptic that may impair wound healing (Leaper 1986). Such comparators are inappropriate when trying to estimate the effect of a therapeutic agent on wound healing. Further trials are justified.

3.2 Pressure ulcers

The effect of honey on pressure ulcers cannot be determined. The included trial was small and lacked sufficient detail to determine risk of bias accurately for most domains. An additional trial has been published as conference abstract (Rucigaj 2006), but without any data. Efforts to contact the author for additional information have not been successful; the trial remains unpublished, to our knowledge, and so has been excluded from the review. Further trials are justified.

3.3 Fournier's gangrene

The effect of honey on Fournier's gangrene cannot be determined. The included trial was small, lacked sufficient detail to determine risk of bias accurately for most domains (although the authors provided information on request), and the comparator was EUSOL, an antiseptic that has been shown to impair wound healing in animal model studies (Brennan 1985). Such comparators are inappropriate when trying to estimate the effect of a therapeutic agent on wound healing. Further trials are justified.

3.4 Cutaneous Leishmaniasis

The unfavourable effect of honey as an adjuvant to meglumine antimoniate on Lieshmaniasis ulcers, while not significantly different from meglumine antimoniate alone, is sufficient to suggest that healing may be delayed and, thus, patients suffer prolonged ulceration. The included trial did lack sufficient detail to determine risk of bias accurately for some domains, but further trials do not seem justified.

3.5 Venous leg ulcers

Combination of two trials at low risk of bias found no significant effect for honey when used as an adjuvant to compression bandaging. The two trials did recruit different populations, with one trial recruiting all comers (Jull 2008), and the other trial restricting participants to those with ulcers that had 50% or more slough coverage (Gethin 2009). Such differences may account for the difference in effect estimates for each trial, although trial size may also account for this difference. The key message, however, is that the evidence does not currently support use of honey dressings as a routine adjuvant to compression, although the possibility of a modest effect cannot be ruled out. Nor can the possibility of an effect in subgroups of patients with venous ulcers, i.e. those with an infected ulcer. Further trials could be justified to quantify such effects.

3.6 Diabetic foot ulcers

The effect of honey on diabetic foot ulcers cannot be determined. The included trial lacked sufficient detail to determine risk of bias for most domains accurately. Further trials are justified.

4. Adverse events

The reporting of adverse events was poor in most trials, and non-existent in a few trials. This makes accurate assessment of the risk of adverse events associated with honey dressings difficult. The International Conference on Harmonization's Guideline for Good Clinical Practice (ICH GCP) defines an adverse event as any untoward medical occurrence in a trial subject who has been administered an intervention, whether related to the intervention or not. With the exception of Jull and colleagues (Jull 2008), it is not clear that any other trial reported all adverse events as required by ICH GCP. Therefore the adverse event findings should be interpreted very cautiously, as the full adverse event profile of honey in different wounds is unknown.

5. Incidence of infection

The use of honey did not significantly decrease infection rates in wounds. The accurate identification of wound infection is a difficult clinical issue in wounds, particularly chronic wounds. Clinical presentation is an important indicator, but presentation may vary with wound type (Cutting 2005), therefore, trialists should remove ambiguity in their definition of infection to ensure that combination of trials in meta-analyses is both feasible and sensible.

Infection is a significant and threatening sequela in burns. Wound sterility after a burn is maintained by careful attention to asepsis during wound care and the use of preventive agents. Honey dressings appear to increase the likelihood that a burn will remain sterile compared with a range of control treatments. These findings, however, are based on censored data. The denominator in all the trials was not the number of participants randomised to the treatment group, but the number of participants with a positive wound swab at baseline. Any future trials of honey dressings for burns should report wound sterility for all participants at baseline, operationally define infection and report the incidence of infection.

6. Cost

Three trials have evaluated the cost of honey as a wound care option, but only one conducted a full cost-effectiveness analysis using a health services perspective (Jull 2008). As the effectiveness of honey was not established by the trial, honey cannot be considered as the dominant strategy.

7. Quality of life

The use of honey in the treatment of venous ulcers had little or no impact on health-related quality of life when measured using SF-36, EQ5D or the Charing Cross Venous Ulcer Questionnaire (Jull 2008).

8. Limitations of this review

This review is subject to a number of limitations. First, the use of mean time to healing is not the most appropriate method of analysing time-to-event data, however, we were limited to using a common means of measurement wherever possible. Second, we attempted to contact authors where the original publication did not provide sufficient data, and then incorporate that data into the review. Where authors did not respond, we excluded the studies that did not report sufficient data even to be included in a narrative analysis. Third, we have retained two analyses where data was combined, despite being highly heterogenous (Analysis 4.1 and Analysis 9.2). A priori decisions to pool trials was made on grounds of clinical and methodological similarity. Our protocol stated that where significant statistical heterogeneity was present, combination of the trials would be by a random-effects model and we would explore sources of heterogeneity. Fourth, it was not possible to evaluate the overall possibility of publication bias, as not all trials reported the same outcomes and overall the trials were too heterogenous to combine.

Authors' conclusions

Implications for practice

Honey dressings do not significantly increase rates of healing in venous leg ulcers at 12 weeks when used as an adjuvant to compression. Honey may delay healing in comparison to early excision and grafting in partial- and full-thickness burns and in cutaneous Leishmaniasis when used as an adjuvant with meglumine antimoniate. Honey might be superior to some conventional dressing materials, but there is considerable uncertainty about the replicability and applicability of this evidence. There is insufficient evidence to guide clinical practice in other areas, and health services may wish to consider avoiding routine use of honey dressings until sufficient evidence of effect is available.

Implications for research

Based on our assessment of the included trials, we make the following recommendations:

  1. Trials should address a research question that addresses a single specific wound aetiology rather than a question that addresses mixed wound aetiologies.

  2. Trials should identify a primary outcome and calculate a sample size using that outcome. The assumptions underpinning the calculations should be incorporated into the trial publications.

  3. Trials should use true randomisation strategies and report the means of generating the allocation sequence and maintaining allocation concealment to the point of randomisation.

  4. Every effort should be made to ensure follow-up is as close to 100% as possible.

  5. Analysis should use the intention-to-treat principle and include all participants in the denominator. Where participants have been lost to follow-up, the report should identify how missing data from those participants was managed e.g. regarded as treatment failures, last value carried forward.

  6. The unit of randomisation and analysis should be participants, not wounds. Studies that randomised and analysed by wound cannot be included in a meta-analysis without artificially inflating the denominator and spuriously improving the precision of the summary statistic. Additionally, randomising by wound breaches the assumption of independent samples that underpins inferential statistics.

  7. Triallists should ensure that the above elements of trial quality are adequately reported, and journals should require that trial reporting is consistent with the Consolidated Statement on Reporting of Trials.

  8. All trials should be registered with a trials register that meets the WHO criteria, and principal investigators should keep their contact details on the register up to date.

Acknowledgements

The reviewers would like to thank the following referees for their comments on the review, Wounds Group Editors: Mieke Flour, Andrea Nelson and Gill Worthy, referees: Margaret Harrison, Lois Orton, Consumer referee: Durhane Wong-Rieger. Anthony Rodgers contributed to the original review but was not involved in the updating of the review, we would like to acknowledge his contribution. Elizabeth Royle copy edited the updated review.

Data and analyses

Download statistical data

Comparison 1. Minor acute wounds
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Time to healing3213Mean Difference (IV, Fixed, 95% CI)1.55 [-1.91, 5.00]
Analysis 1.1.

Comparison 1 Minor acute wounds, Outcome 1 Time to healing.

Comparison 2. Partial-thickness burns - honey vs conventional dressings
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Time to healing (days)2992Mean Difference (IV, Fixed, 95% CI)-4.68 [-5.09, -4.28]
Analysis 2.1.

Comparison 2 Partial-thickness burns - honey vs conventional dressings, Outcome 1 Time to healing (days).

Comparison 3. Burns - honey vs early excision & grafting
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Early excision & grafting150Mean Difference (IV, Fixed, 95% CI)13.60 [10.02, 17.18]
Analysis 3.1.

Comparison 3 Burns - honey vs early excision & grafting, Outcome 1 Early excision & grafting.

Comparison 4. Burns - honey vs silver sulfadiazine (SSD)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Time to healing (days)3254Mean Difference (IV, Random, 95% CI)-4.37 [-8.94, 0.19]
Analysis 4.1.

Comparison 4 Burns - honey vs silver sulfadiazine (SSD), Outcome 1 Time to healing (days).

Comparison 5. Burns - honey vs unconventional dressings
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Time to healing (days)3 Mean Difference (IV, Random, 95% CI)Totals not selected
Analysis 5.1.

Comparison 5 Burns - honey vs unconventional dressings, Outcome 1 Time to healing (days).

Comparison 6. Mixed acute and chronic wounds
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Time to healing (days)1100Mean Difference (IV, Fixed, 95% CI)-13.0 [-15.24, -10.76]
2 Proportion healed1105Risk Ratio (M-H, Fixed, 95% CI)1.14 [0.88, 1.48]
Analysis 6.1.

Comparison 6 Mixed acute and chronic wounds, Outcome 1 Time to healing (days).

Analysis 6.2.

Comparison 6 Mixed acute and chronic wounds, Outcome 2 Proportion healed.

Comparison 7. Chronic wounds
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Time to healing (days)3 Mean Difference (IV, Fixed, 95% CI)Totals not selected
1.1 Infected postoperative wounds1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 Pressure ulcers1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
1.3 Fournier's gangrene1 Mean Difference (IV, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Proportion healed3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Leishmaniasis190Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.51, 1.01]
2.2 Venous leg ulcers2476Risk Ratio (M-H, Fixed, 95% CI)1.15 [0.96, 1.38]
Analysis 7.1.

Comparison 7 Chronic wounds, Outcome 1 Time to healing (days).

Analysis 7.2.

Comparison 7 Chronic wounds, Outcome 2 Proportion healed.

Comparison 8. Adverse events
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 All adverse events12 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Minor acute wounds182Risk Ratio (M-H, Random, 95% CI)1.37 [0.77, 2.45]
1.2 Burns71390Risk Ratio (M-H, Random, 95% CI)0.77 [0.31, 1.92]
1.3 Infected post-operative wounds150Risk Ratio (M-H, Random, 95% CI)0.31 [0.11, 0.82]
1.4 Fournier's gangrene130Risk Ratio (M-H, Random, 95% CI)0.57 [0.06, 5.65]
1.5 Venous leg ulcers1368Risk Ratio (M-H, Random, 95% CI)1.28 [1.05, 1.56]
1.6 Wounds healing by secondary intention1105Risk Ratio (M-H, Random, 95% CI)2.04 [0.39, 10.65]
Analysis 8.1.

Comparison 8 Adverse events, Outcome 1 All adverse events.

Comparison 9. Incidence of infection
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of clinically diagnosed infection4627Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.50, 1.04]
2 Burns patients with positive swab cultures at admission rendered sterile after 7 days treatment7522Risk Ratio (M-H, Random, 95% CI)5.31 [1.75, 16.18]
Analysis 9.1.

Comparison 9 Incidence of infection, Outcome 1 Incidence of clinically diagnosed infection.

Analysis 9.2.

Comparison 9 Incidence of infection, Outcome 2 Burns patients with positive swab cultures at admission rendered sterile after 7 days treatment.

Appendices

Appendix 1. Search Methods for Original Review - 2008

Electronic searches

Searches of the following electronic databases were undertaken:

Cochrane Wounds Group Specialised Register (Searched 27/5/08)
The Cochrane Central Register of Controlled Trials (CENTRAL) - The Cochrane Library Issue 2 2008
Ovid MEDLINE - 1950 to May Week 2 2008
Ovid EMBASE - 1980 to 2008 Week 21
Ovid CINAHL - 1982 to May Week 4 2008

The following search strategy was used in the CENTRAL and adapted where appropriate for other databases :

#1 MeSH descriptor Skin Ulcer explode all trees
#2 MeSH descriptor Pilonidal Sinus explode all trees
#3 MeSH descriptor Wounds, Penetrating explode all trees
#4 MeSH descriptor Lacerations explode all trees
#5 MeSH descriptor Burns explode all trees
#6 MeSH descriptor Wound Infection explode all trees
#7 MeSH descriptor Surgical Wound Dehiscence explode all trees
#8 MeSH descriptor Bites and Stings explode all trees
#9 MeSH descriptor Cicatrix explode all trees
#10 ((plantar or diabetic or heel* or foot or feet or ischaemic or ischemic or venous or varicose or stasis or arterial or decubitus or pressure or skin or leg or mixed or tropical or rheumatoid or sickle
cell) NEAR/5 (wound* or ulcer*)):ti,ab,kw
#11 (bedsore* or (bed NEXT sore*)):ti,ab,kw
#12 (pilonidal sinus* or pilonidal cyst*):ti,ab,kw
#13 (cavity wound* or sinus wound*):ti,ab,kw
#14 (laceration* or gunshot stab or stabbing or stabbed or bite*):ti,ab,kw
#15 ("burn" or "burns" or "burned" or scald*):ti,ab,kw
#16 (surg* NEAR/5 infection*):ti,ab,kw
#17 (surg* NEAR/5 wound*):ti,ab,kw
#18 (wound* NEAR/5 infection*):ti,ab,kw
#19 (malignant wound* or experimental wound* or traumatic wound*):ti,ab,kw
#20 (infusion site* or donor site* or wound site* or surgical site*):ti,ab,kw
#21 (skin abscess* or skin abcess*):ti,ab,kw
#22 (hypertrophic scar* or keloid*):ti,ab,kw
#23 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR
#12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22)
#24 MeSH descriptor Honey explode all trees
#25 honey:ti,ab,kw
#26 (#24 OR #25)
#27 (#23 AND #26)

The MEDLINE search was combined with the Cochrane Highly Sensitive Search Strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximizing version (2008 revision); Ovid format. The EMBASE and CINAHL searches were combined with the trial filters developed by the Scottish Intercollegiate Guidelines Network. Additionally, LILACS (1982 to October 2006), AMED (1985 to October 2006) and Google Scholar were searched using the text word "honey".

Searching other resources

Contact was made with experts in the field, authors of the included trials and manufacturers of honey products for wound care (Comvita NZ Ltd and MediHoney Australia Pty Ltd). The bibliographies of all obtained studies and review articles were searched for potentially eligible trials. No language or date restrictions were applied to the trials and both published and unpublished trials were sought.

Appendix 2. Search strategies for Medline, Embase and CINAHL

Ovid Medline

1 exp Skin Ulcer/ (18230)
2 exp Pilonidal Sinus/ (543)
3 exp Wounds, Penetrating/ (14308)
4 exp Lacerations/ (1423)
5 exp Burns/ (17087)
6 exp Wound Infection/ (14097)
7 exp Surgical Wound Dehiscence/ (2829)
8 exp "Bites and Stings"/ (7739)
9 exp Cicatrix/ (13623)
10 ((plantar or diabetic or heel$ or foot or feet or ischaemic or ischemic or venous or varicose or stasis or arterial or decubitus or pressure or skin or leg or mixed or tropical or rheumatoid or sickle cell) adj5 (wound$ or ulcer$)).ti,ab. (18800)
11 (bedsore$ or bed sore$).ti,ab. (239)
12 (pilonidal sinus$ or pilonidal cyst$).ti,ab. (437)
13 (cavity wound$ or sinus wound$).ti,ab. (37)
14 (laceration$ or gunshot or stab or stabbing or stabbed or bite$).ti,ab. (19976)
15 (burn or burns or burned or scald$).ti,ab. (19171)
16 (surg$ adj5 wound$).ti,ab. (5431)
17 (surg$ adj5 infection$).ti,ab. (8723)
18 (wound adj5 infection$).ti,ab. (10745)
19 (malignant wound$ or experimental wound$ or traumatic wound$).ti,ab. (428)
20 (infusion site$ or donor site$ or wound site$).ti,ab. (7460)
21 (skin abscess$ or skin abcess$).ti,ab. (162)
22 (hypertrophic scar$ or keloid scar$).ti,ab. (1595)
23 or/1-22 (130992)
24 exp Honey/ (1328)
25 honey.ti,ab. (3036)
26 or/24-25 (3160)
27 23 and 26 (249)

Ovid Embase

1 exp Skin Ulcer/ (30058)
2 exp Pilonidal Sinus/ (883)
3 exp Penetrating Trauma/ (5303)
4 exp Laceration/ (4283)
5 exp Skin Abrasion/ (2135)
6 exp Burns/ (25289)
7 exp Wound Infection/ (17999)
8 exp Surgical Wound/ (3060)
9 exp Wound Dehiscence/ (6273)
10 exp Bite Wound/ (340)
11 exp Scar/ (28923)
12 ((plantar or diabetic or heel$ or foot or feet or ischaemic or ischemic or venous or varicose or stasis or arterial or decubitus or pressure or skin or leg or mixed or tropical or rheumatoid or sickle cell) adj5 (wound$ or ulcer$)).ti,ab. (26847)
13 (bedsore$ or bed sore$).ti,ab. (397)
14 (pilonidal sinus$ or pilonidal cyst$).ti,ab. (628)
15 (cavity wound$ or sinus wound$).ti,ab. (50)
16 (laceration$ or gunshot or stab or stabbing or stabbed or bite$).ti,ab. (26569)
17 (burn or burns or burned or scald$).ti,ab. (26981)
18 (surg$ adj5 wound$).ti,ab. (7562)
19 (surg$ adj5 infection$).ti,ab. (12748)
20 (wound adj5 infection$).ti,ab. (15320)
21 (malignant wound$ or experimental wound$ or traumatic wound$).ti,ab. (559)
22 (infusion site$ or donor site$ or wound site$).ti,ab. (9548)
23 (skin abscess$ or skin abcess$).ti,ab. (278)
24 (hypertrophic scar$ or keloid scar$).ti,ab. (2338)
25 or/1-24 (183396)
26 exp Honey/ (2368)
27 honey.ti,ab. (4323)
28 or/26-27 (4693)
29 25 and 28 (337)

EBSCO CINAHL

S29 S25 and S28
S28 S26 or S27
S27 TI honey or AB honey
S26 (MH "Honey")
S25 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16 or S17 or S18 or S19 or S20 or S21 or S22 or S23 or S24
S24 TI ( hypertrophic scar* or keloid scar* ) or AB ( hypertrophic scar* or keloid scar* )
S23 TI ( skin abscess* or skin abcess* ) or AB ( skin abscess* or skin abcess* )
S22 TI ( infusion site* or donor site* or wound site* ) or AB ( infusion site* or donor site* or wound site* )
S21 TI ( malignant wound* or experimental wound* or traumatic wound* ) or AB ( malignant wound* or experimental wound* or traumatic wound* )
S20 TI wound* N5 infect* or AB wound* N5 infect*
S19 TI surg* N5 infection* or AB surg* N5 infection*
S18 TI surg* N5 wound* or AB surg* N5 wound*
S17 TI ( burn or burns or burned or scald* ) or AB ( burn or burns or burned or scald* )
S16 TI (laceration* or gunshot or stab or stabbing or stabbed or bite*) or AB (laceration* or gunshot or stab or stabbing or stabbed or bite*)
S15 TI ( cavity wound* or sinus wound* ) or AB ( cavity wound* or sinus wound* )
S14 TI ( pilonidal sinus* or pilonidal cyst* ) or AB ( pilonidal sinus* or pilonidal cyst*)
S13 TI ( bedsore* or bed sore* ) or AB ( bedsore* or bed sore* )
S12 AB ( plantar or diabetic or heel* or foot or feet or ischemia or ischemic or venous or varicose or stasis or arterial or crural or decubitus or pressure or skin or leg or mixed or tropical or rheumatoid or sickle cell ) and AB ulcer*
S11 TI ( plantar or diabetic or heel* or foot or feet or ischemia or ischemic or venous or varicose or stasis or arterial or crural or decubitus or pressure or skin or leg or mixed or tropical or rheumatoid or sickle cell ) and TI ulcer*
S10 (MH "Cicatrix+")
S9 (MH "Bites and Stings+")
S8 (MH "Surgical Wound Dehiscence")
S7 (MH "Surgical Wound")
S6 (MH "Wound Infection+")
S5 (MH "Burns+")
S4 (MH "Tears and Lacerations")
S3 (MH "Wounds, Penetrating+")
S2 (MH "Diabetic Foot")
S1 (MH "Skin Ulcer+")

Appendix 3. Risk of bias assessment criteria

1.  Was the allocation sequence randomly generated?

Low risk of bias

The investigators describe a random component in the sequence generation process such as: referring to a random number table; using a computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots.

High risk of bias

The investigators describe a non-random component in the sequence generation process. Usually, the description would involve some systematic, non-random approach, for example: sequence generated by odd or even date of birth; sequence generated by some rule based on date (or day) of admission; sequence generated by some rule based on hospital or clinic record number.

Unclear

Insufficient information about the sequence generation process to permit judgement of Yes or No, as above.

2.  Was the treatment allocation adequately concealed?

Low risk of bias

Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: central allocation (including telephone, web-based and pharmacy-controlled randomisation); sequentially-numbered drug containers of identical appearance; sequentially-numbered, opaque, sealed envelopes.

High risk of bias

Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes without appropriate safeguards (e.g. envelopes that were unsealed, non-opaque or not numbered sequentially); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

Unclear

Insufficient information to permit judgement of Yes or No, as above. This is usually the case if the method of concealment is not described, or not described in sufficient detail to allow a definite judgement, for example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially-numbered, opaque and sealed.

3.  Blinding was knowledge of the allocated interventions adequately prevented during the study?

Low risk of bias

Any one of the following:

  • No blinding, but the review authors judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding.

  • Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.

  • Either participants or some key study personnel were not blinded, but outcome assessment was blinded and the non-blinding of others was unlikely to introduce bias.

High risk of bias

Any one of the following:

  • No blinding, or incomplete blinding, and the outcome or outcome measurement was likely to be influenced by lack of blinding.

  • Blinding of key study participants and personnel attempted, but likely that the blinding could have been broken.

  • Either participants or some key study personnel were not blinded, and the non-blinding of others was likely to introduce bias.

Unclear

Either of the following:

  • Insufficient information to permit judgement of Yes or No, as above.

  • The study did not address this outcome.

4.  Were incomplete outcome data adequately addressed?

Low risk of bias

Any one of the following:

  • No missing outcome data.

  • Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias).

  • Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups.

  • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not high enough to have a clinically relevant impact on the intervention effect estimate.

  • For continuous outcome data, plausible effect size (difference in means or standardised difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size.

  • Missing data have been imputed using appropriate methods.

High risk of bias

Any one of the following:

  • Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups.

  • For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk is high enough to induce clinically relevant bias in intervention effect estimate.

  • For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size.

  • As-treated analysis done with substantial departure of the intervention received from that assigned at randomisation.

  • Potentially inappropriate application of simple imputation.

 Unclear

Either of the following:

  • Insufficient reporting of attrition/exclusions to permit judgement of Yes or No, as above (e.g. number randomised not stated, no reasons for missing data provided).

  • The study did not address this outcome.

5.  Are reports of the study free of suggestion of selective outcome reporting?

Low risk of bias

Either of the following:

  • The study protocol is available and all of the study's pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way.

  • The study protocol is not available, but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).

High risk of bias

Any one of the following:

  • Not all of the study's pre-specified primary outcomes have been reported.

  • One or more primary outcomes reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified.

  • One or more reported primary outcomes not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect).

  • One or more outcomes of interest in the review reported incompletely so that they cannot be entered in a meta-analysis.

  • The study report fails to include results for a key outcome that would be expected to have been reported for such a study.

Unclear

Insufficient information to permit judgement of Yes or No, as above. It is likely that the majority of studies will fall into this category.

6.  Other sources of potential bias:

Low risk of bias

The study appears to be free of other sources of bias.

High risk of bias

There is at least one important risk of bias. For example, the study:

  • had a potential source of bias related to the specific study design used; or

  • stopped early due to some data-dependent process (including a formal-stopping rule); or

  • had extreme baseline imbalance; or

  • has been claimed to have been fraudulent; or

  • had some other problem.

Unclear

There may be a risk of bias, but there is either:

  • insufficient information to assess whether an important risk of bias exists; or

  • insufficient rationale or evidence that an identified problem will introduce bias.

Feedback

Authors' conclusions, 14 June 2013

Summary

Email received from Barry Wolfenson on behalf of Derma Sciences expressing concern at the wording of the Authors' conclusions - as follows:
“There is insufficient evidence to guide clinical practice in other types of wounds, and purchasers should refrain from providing honey dressings for routine use until sufficient evidence of effect is available.”

Reply

Andrew Jull, Author; Nicky Cullum, Coordinating Editor CWG; Sally Bell-Syer Managing Editor CWG.

Thank you for your feedback. this statement has been present in the Authors' conclusions since the review was first published in 2008. However this is a valid point and does contravene Cochrane guidance from the Handbook which states " The primary purpose of the review should be to present information, rather than to offer advice". As a result we have modified this section to read: "There is insufficient evidence to guide clinical practice in other areas, health services may wish to consider avoiding routine use of honey dressings until sufficient evidence of effect is available"

Contributors

Barry J. Wolfenson, Group President, Advanced Wound Care & Drug Development, Derma Sciences.
Andrew Jull, Author; Nicky Cullum, Coordinating Editor CWG; Sally Bell-Syer Managing Editor CWG.

Feedback questions from Derma Sciences, 4 September 2013

Summary

Email received from Barry Wolfenson, Group President, Advanced Wound Care & Drug Development, Derma Sciences.

Q1. Can you please let me know, regarding the 132 Cochrane Reviews on the topic of Wounds, aside from the one titled “Honey as a topical treatment for wounds”, how many include studies within the review that are authored by authors of the Cochrane Review itself?

Authors response: This is a very general question; you have not identified the 132 reviews you are referring to and we do not routinely record that information outside of the review. However, any included trial which has a trialist who is also an author of the Cochrane review must declare this in the Declaration of Interests section of the review.

Q2. Given that one of your stated core principles is to minimize bias, can you please let me know your organizational guidelines regarding authorship of reviews and whether or not authors should be able to review their own studies? To a lay person, there seems to be quite a potential for conflict here.

Authors response: In the Cochrane Wounds Group we adhere strictly to the policy that if an author of a Cochrane review is also a trialist of an included trial in that same review they must declare this in the Declaration of Interests section of the review. This declaration is also made in the online Declaration of Interests form which has to be completed by all authors before a protocol or a review can be published on the Cochrane Library.

Q3. As reviewers of the Jull et al study (Randomized clinical trial of honey-impregnated dressings for venous leg ulcers), how did you judge the relative bias of the study author’s ad hoc decision to remove incidence of infections from the adverse events table?

Authors response: This question is directly with respect to a trial we conducted, not the systematic review. We did not remove incidence of infections from adverse events. The incidence of infection was analysed separately as specified a priori in the protocol and statistical analysis plan in response to interest in whether honey may prevent infections in venous leg ulcers.

Q4. With regard to the above, the removal of infections from the adverse events section somehow allowed the study authors to also remove the costs associated with hospitalizations associated with those infections from their overall cost of care analysis. However, the other costs associated with hospitalization (not having to do with infection) remained. When the costs associated with hospitalizations due to infection were included in the analysis, the honey arm was less expensive. Only after the costs associated with the additional hospitalizations associated with infection were removed (ad hoc) was the honey arm more expensive. Given that the decision to remove infections was ad hoc, how did you judge the relative bias of the statement by the study authors that the honey arm was likely more expensive?

Authors response: This question is directly with respect to a trial we conducted, not the systematic review. Incidence of infection was included in all the cost analyses. An analysis for sensitivity of the base case (all costs for ulcer treatment) to the small number of patients hospitalized for treatment related to their ulcer was undertaken. We do not know what the exact purpose of the hospitalization was ie whether it was related to infection or not, only that it was self-reported by the patients as related to their ulcer. As explained in the paper, the difference was likely due to random variability rather than use of honey or not. The decision to sensitivity test the base case was not ad hoc.

Q5. As reviewers of the Jull et al study, how did you judge the relative bias of the study regarding the author’s conclusion that honey dressings should not be considered for venous leg ulcer healing given that all the primary and secondary endpoints favored the honey arm (although not statistically)? It would seem, based on the results of the study, that honey should be included into the control group of alginate, hydrofiber, hydrocolloid, foam, non-adherent, iodine, and silver-based dressings as dressings that have demonstrated efficacy as adjuvants to compression therapy. Again, given the positive nature of the evidence derived in this study, how did you judge the potential bias within the authors’ conclusion?

Authors response: This question is directly with respect to a trial we conducted, not the systematic review. There were no statistically significant differences between the groups on the primary outcome, nor on any of the secondary outcomes. In fact the results for the blinded verification of healing suggest barely any difference between groups (absolute difference 0.5%, 95%CI -10.6% to 11.3%) on the primary outcome. Routine use of honey dressings is therefore not superior to other dressings for promoting healing compared to usual care. This conclusion does not preclude non-routine use of honey.

Q6. You included a second study in your Cochrane Review to address the management of venous leg ulcers. This second study, by Gethin et al, allowed only those wounds with greater than 50% slough coverage. In the larger Jull et al study of potentially likely to heal venous leg ulcers, the authors stated that the positive results (not statistically significant) favoring honey should be “generalizable” to all venous leg ulcers, regardless of wound bed appearance, unless new data shows otherwise. In the Gethin study, the wounds in both arms had average slough coverage ranging from 78% - 86%, and had average wound areas of 9.9cm2 to 10.5cm2. However, in the Jull study, there is no notation of slough coverage and the wounds ranged in average area from only 2.6cm2 to 2.7cm2. Thus, the wound bed appearance was dramatically different between these two studies. If the authors of the Jull study thought it was wise to view different wound bed appearance as indicative of a different patient set, why did you chose to combine results of these two vastly different studies? It should be noted that in the Gethin study on harder-to-heal wounds, even a much smaller number of patients resulted in the honey arm providing statistically significant healing benefit over control. Based on what the authors of the Jull et al study stated, shouldn’t your conclusions from these two studies have been: Honey provides a non-significant healing benefit for routine venous leg ulcers, and provides a significant healing benefit for non-routine venous leg ulcers?

Authors response: The commentator states two studies were “vastly different” but mistakenly compares median ulcer size reported in Jull et al to mean ulcer size reported in Gethin & Cowman, two statistics that are not comparable. The median ulcer area reported in Gethin & Cowman was 5.4 and 4.2 cm2. Ulcer duration is also an important consideration when considering likelihood of healing. The mean duration of ulceration prior to enrolment in the Gethin and Cowman study was 39 weeks and 30 weeks, which was similar to the means in Jull et al (39 and 48 weeks). To suggest therefore that Gethin & Cowman recruited harder-to-heal wounds compared to Jull et al is not accurate. These studies were not dissimilar in terms of populations and there is no evidence to suggest that they were different in terms of wound bed appearance – one trial provided information on this factor, another did not. In the Gethin & Cowman study, the statistically significant difference only emerged in the adjusted analysis. The unadjusted analysis for Gethin and Cowman is presented in the systematic review and shows no significant difference (RR 1.33, 95%CI 0.82 – 2.16).

Q7. Regarding honey versus SSD, why should the results of these studies be disregarded as you suggest due to other studies having shown benefit of hydrocolloids and silicone based dressings over SSD? Does this mean that you recommend that no other studies be done comparing one arm to SSD in the treatment of partial thickness burns?

Authors response: There is evidence that suggests SSD cream applied from time treatment initiated until healing may delay healing. (Thomas SS et al. J Wound Care 1995;4:218-20. Wyatt D et al. J Trauma 1990;30:857-65. Bugmann P et al. Burns 1998;24:609-12.) It appears the issue may be how SSD cream is used, not whether it is used. Our focus in the review was in trying to understand whether honey conferred a benefit. Using an appropriate comparator is pertinent to such an analysis and it is not clear that SSD applied daily from treatment initiation to healing is an appropriate comparator.

Q8. Regarding the above, which do you think is the more commonly used product on partial thickness burns, SSD or hydrocolloids? Are you aware of the commonplace usage on SSD in burn centers? If so, why would you suggest disregarding the results of studies which show a benefit over SSD? If not, and you find this to be true (that SSD is still commonly used in burn centers), would you change your decision to disregard the evidence derived from studies utilizing SSD as a control arm?

Authors response: See above

Q9. Also regarding the honey vs SSD studies, can you provide a more thorough clarification on why the CHIT method employed by the investigator disqualified these studies from your analysis?

Authors response: The use of the chit method did not disqualify any trial from consideration. Authors of trials that did not describe the method for generating the random sequence were approached for further information. The author of 11 trials replied stating the sequence was “manually generated random numbers by the chit method”, without providing any further information about what was meant by this approach with respect to sequence generation. We sought the advice of broadly experienced senior biostatistician who could not infer from this response what method of sequence generation was used. We therefore stated in the Risk of bias tables “method of generation of random sequence not reported. The author informed us that the sequence was generated by the ‘chit method’, but it is not clear what this method is.”

Q10. Of the 6 additional studies cited as rationale for this “updated” Cochrane Review, 5 out of the 6 are positive in favor of honey. Why is only the one negative study included in your updated conclusion? How did the biases of this study, as well as the overall structure of the study, compare with the other 5 studies which were not included in your updated conclusion? Were these differences the reason you only cited the negative study?

Authors response: When a review is updated we run the searches again and assess the resulting output. For this update we identified six additional studies which met the inclusion criteria published in the review, and all six studies were included in the review with the results of those studies presented.

Q11. Would someone be wrong if they stated it appears as though your inclusion of only the one negative study, and lack of inclusion of the 5 positive studies, appears to be “cherry picking”?

Authors response: A systematic review is conducted according to a defined, peer reviewed and published protocol to minimize bias. Any studies which are excluded have to be identified in the Table of Excluded studies and the reasons for the exclusion made clear. I am assuming you are referring to the six additional studies which were included in the last update of this review. All six studies are “included studies”.

Q12. Regarding the one negative study, which was on the treatment of cutaneous Leishmaniasis (a wound resulting from a bite from a sand fly indigenous to the Middle East), the study authors note that further studies should be done using standardized medical grade honeys, such as Leptospermum Scoparium (Manuka Honey). They acknowledge the fact that they used plain local honey could have been the reason for not achieving positive results. Why did you not include this in your conclusions or anywhere in your description of the study?

Authors response: The purpose of the review was to summarise the available evidence, not to restate authors’ interpretations.

Q13. Regarding the negative study on honey vs early excision and grafting of mixed partial and full thickness ulcers, to the best of your knowledge, how many studies do you know that compare one dressing vs this surgical standard and show improved results? Given the rest of the consistently positive results of the other honey studies cited for management of partial thickness burns, do you think the results of the early excision and grafting study suggest that honey would in any way be dangerous to use on partial thickness wounds that do not require early excision and grafting? If so, why?

Authors response: This review does not set out to present results of any dressing when compared with early excision and grafting of mixed partial and full thickness ulcers. Clearly there was sufficient equipoise for a trial to be conducted comparing early excision and grafting versus treatment with honey and delayed grafting as necessary. This trial was therefore included in the review.

Q14. Can you please provide the total numbers of the following: How many studies cited in your review had a statistically significantly positive outcome for the honey arm? How many studies cited in your review had a positive outcome (although not significantly) for the honey arm? How many studies had a negative outcome (although not significantly) for the honey arm? How many studies had a statistically significantly negative outcome for the honey arm?

Authors response: The data extracted from the trials and presented in the results section is provided in the review. Counting the number of statistically significant studies is not a sensible approach to summarising evidence when meta-analysis is possible.

Q15. Given the numbers above, why did you feel that it was important to include in your updated conclusion the following statement; “…purchasers should refrain from providing honey dressings for routine use until sufficient evidence of effect is available”? This statement seems cautionary in its advice. What is the caution that you believe purchasing agents should take into account when considering routine use of honey based dressings?

Authors response: In the light of insufficient evidence a cautionary approach is warranted. Routine use of honey dressings refers to use of honey as a first line dressing.

Q16. Given that Andrew Jull is not only is the author of the key study cited in the Cochrane Review, but that he is also on the editorial board for the wounds group reviewing all Cochrane Reviews on wound care, this question is directed specifically to him in his role as an editor: Due to the lack of well controlled RCTs, the vast majority of Cochrane Reviews on wound dressings / technologies (with the exception of total contact casts) have negative conclusions. The majority of these conclusions all seem to have a “boiler plate” type of statement, basically stating “there is not enough evidence to suggest the use of one product over another.” Given the recent updated conclusion in the review of honey dressings, do you think, if any of the other reviews are similarly “updated” (including those on negative pressure, silver based dressings, alginates, hydrocolloids, foams, etc.), without any meaningful positive results from well controlled studies, do you think that clinicians should similarly be advised to refrain from routine use of those dressings/technologies for routine use until sufficient evidence of effect is available? If not, then why?

Authors response: Andrew Jull is an Editor of the Cochrane Wounds Group; he does not review all Cochrane reviews in wound care and reviews are distributed amongst all the editors and each review is peer reviewed by a number of editors and reviewers. It is not appropriate for the authors of this review to suggest how other authors should write their reviews.

Q17. Why was the statement, “purchasers should refrain from providing honey dressings for routine use until sufficient evidence of effect is available” subsequently changed?

Authors response: This change was in response to feedback received from Barry Wolfenson on behalf of Derma Sciences (14th June 2013) expressing concern at the wording of the Authors' conclusions - as follows: “There is insufficient evidence to guide clinical practice in other types of wounds, and purchasers should refrain from providing honey dressings for routine use until sufficient evidence of effect is available.” This statement had been present in the Authors' conclusions since the review was first published in 2008. Cochrane guidance from the Handbook states "The primary purpose of the review should be to present information, rather than to offer advice". Having considered the feedback and received the advice of the Cochrane Collaboration, we have modified this section to read: "…There is insufficient evidence to guide clinical practice in other areas, and health services may wish to consider avoiding routine use of honey dressings until sufficient evidence of effect is available". Although the primary purpose of a review is to present information, rather than to offer advice, review authors are invited to interpret the findings of their review in the "implications for practice" section. This section is clearly labelled as "authors' conclusions".

Q18. Do you believe the following statement is intended to provide advice; “…Health services may wish to consider avoiding routine use of honey dressings until sufficient evidence of effect is available”? If not, how do you interpret this statement to not be providing advice on usage?

Authors response: Review authors are invited to interpret the findings of their review in the "implications for practice" section and these are clearly labelled as "authors' conclusions". It seems perfectly reasonable where no compelling evidence of benefit has been identified to suggest that decision makers consider this finding. The use of the terms "consider" and "routine" clearly indicate that this is not intended to be a didactic recommendation, simply something for consideration by decision makers.

Q19. How many times is this type of advice given in any of the other Cochrane Reviews regarding wound dressings? Please only limit your response to those Cochrane Reviews that had negative conclusions, such as on alginates, foams, silver dressings, negative pressure, etc… If the answer is 0 (zero), what do you think is the distinction between the evidence presented for honey-based dressings and the evidence presented for these other dressings/technologies?

Authors response: There is no blueprint for the precise wording of this section, and it is not unusual for Cochrane Reviews to present text that provides guidance that decision makers should consider the absence of high quality evidence of benefit when making treatment decisions.

Q20. Specifically regarding your statement in the Cochrane Review that clinicians may consider refraining from routine use on honey-based dressings, can you please clarify:

20.1 For routine venous leg ulcers: Should clinicians refrain from using honey-based dressings? If so, why?

Authors response: It is reasonable to highlight the apparent failure of routine use honey dressings to deliver such an important outcome as healing rate.

20.2 For chronic/stalled venous leg ulcers: Should clinicians refrain from using honey-based dressings? If so, why?

Authors response: All venous leg ulcers are chronic. The evidence from the trials does not address “stalled” venous ulcers.

20.3 For other routine ulcers such as pressure ulcers: Should clinicians refrain from using honey-based dressings? If so, why?

Authors response: The results of the review demonstrate clear uncertainty in respect of this outcome.

20.4 For other chronic/stalled ulcers such as pressure ulcers: Should clinicians refrain from using honey-based dressings? If so, why?

Authors response: The evidence from the single available trial does not address “stalled” pressure ulcers.

20.5 For partial thickness burns that do not require early excision and grafting: Should clinicians refrain from using honey-based dressings? If so, why?

Authors response: The results of the review demonstrate clear uncertainty in respect of this outcome.

20.6 For any challenging wounds where a clinician would typically use negative pressure, silver-based dressings, iodine-based dressings, alginates, or foams: Should clinicians refrain from using honey-based dressings? If so, why?

Authors response: There were no trials where the wounds were defined as ‘challenging’.

20.7 Do you consider chronic wounds (whether they be venous leg ulcers, diabetic foot ulcers, pressure ulcers, or dehisced surgical wounds) to be “routine”?

Authors response: It is not clear what is meant by “routine” in this context – none of the conditions are uncommon.

20.8 Do you consider partial thickness burns that are treated in a burn center to be “routine”?

Authors response: It is not clear what is meant by “routine” in this context.

Reply

The authors of the review have responded to this feedback giving a point by point response to the questions above.

Contributors

Barry Wolfenson, Group President, Advanced Wound Care & Drug Development, Derma Sciences.
Declaration of interest: I am the President of Advanced Wound Care at Derma Sciences. Thus, I clearly have involvement with an organization with a financial interest in the subject matter of my feedback.

Andrew Jull, Author; Nicky Cullum, Coordinating Editor CWG; Sally Bell-Syer Managing Editor CWG.

Feedback questions from Laura Bolton, 27 September 2013

Summary

Comment: I strongly support evidence-based practice and was trained as a Cochrane reviewer in 1995. Am concerned that this SR is eroding Cochrane credibility as so many wound care professionals have asked me to clarify issues in it. Please help correct the following errors as quickly and thoroughly as possible:
1. Errors in describing the studies (omission of important facts or perspective),
2. Arbitrary emphasis on non-statistically significant or irrelevant or inappropriate findings in abstract and conclusions
3. Omitting statistically significant RCT healing results favorable to honey in abstract and conclusions
4. Statements in the Authors conclusion and Abstract do not seem to reflect the results reported in the body of the SR
5. Inappropriate recommendations to avoid honey use that usurp clinician's point of care decisions rather than inform them of level of evidence supporting honey use for various indications, which appears no less sufficient than that for many other wound care interventions.
My Cochrane trainers insisted we avoid recommending and simply describe levels of evidence to empower clinical decision making. Has this changed?
To clarify the issues Dr. Janice Beitz and I presented a webinar with more detail on each issue accessible at:
http://www.dermasciences.com/pdf/Scientific-Review-of-Cochrane-Review-Honey-as-Topical-Treatment-for-Wounds-Dr.-Bolton-and-Dr.%20Beitz.pdf
Thank you and the hard working Cochrane Wounds Group for your immediate attention to help uphold Cochrane credibility!

Reply

The authors of the review are considering the feedback.

Contributors

Laura Bolton, Adjunct Associate Professor of Surgery, Rutgers University Medical School.
Declaration of interest: I certify that I consult on evidence-based product development and study design for EuroMed, Derma Sciences and Systagenix, but have never received any corporate funding for honey-related consulting or speaking nor for my part in presenting the Webinar described.

What's new

Last assessed as up-to-date: 13 June 2012.

DateEventDescription
4 February 2014Feedback has been incorporatedResponse to feedback

History

Protocol first published: Issue 1, 2005
Review first published: Issue 4, 2008

DateEventDescription
3 October 2013Feedback has been incorporatedFeedback received, author team to respond
19 June 2013Feedback has been incorporatedText edits in response to feedback
13 June 2012New citation required and conclusions have changedSix additional studies included (Baghel 2009; Mashood 2006; Memon 2005; Nilforoushzadeh 2007; Robson 2009; Shukrimi 2008), conclusions updated. New author contributed to the review update (Sohan Deshpande) and Anthony Rodgers who contributed to the original review has not contributed to the update.
13 June 2012New search has been performedNew search, risk of bias assessment completed on all included studies; primary reference for Gethin 2007 changed to Gethin 2009.
11 August 2009AmendedContact details updated.
13 May 2009AmendedContact details updated.
28 March 2008AmendedConverted to new review format.

Contributions of authors

Andrew Jull: designed and co-ordinated the review. Extracted data (first review), reviewed risk of bias assessments and data extraction (this update). Analysed or interpreted data and performed statistical analysis, wrote to study author/experts/companies, completed the drafts, revisions, and the final review (first review and this update). He is guarantor of the review.
Natalie Walker: designed the review and checked studies to be included, checked risk of bias assessment and the quality of statistical analysis (first review), performed part of writing or editing of the review (first review and this update). Approved final review prior to submission (first review and this update).
Sohan Deshpande: checked studies to be included, extracted data, performed risk of bias assessments and contributed to writing (this update).

Contributions of editorial base:

Nicky Cullum: edited the review, advised on methodology, interpretation and review content; approved the final review prior to submission.
Liz McInnes, Editor: approved the review update prior to submission.
Sally Bell-Syer: co-ordinated the editorial process; advised on methodology, interpretation and content; edited the review and the updated review.
Ruth Foxlee: designed the search strategy and edited the search methods section.

Declarations of interest

Andrew Jull, Natalie Walker and Anthony Rodgers were investigators in the Honey as Adjuvant Leg ulcer Treatment (HALT) trial (ISRCTN 06161544), one of the trials included in this review. The Clinical Trials Research Unit, which employed Andrew Jull, Natalie Walker and Antony Rodgers received a small, unconditional cash contribution from a manufacturer of honey dressings for the conduct of the HALT trial.

Sources of support

Internal sources

  • Senior Health Research Scholarship, University of Auckland, New Zealand.

External sources

  • NIHR/Department of Health (England), (Cochrane Wounds Group), UK.

Differences between protocol and review

In the first version of the review, two trials that compared active interventions allocated wounds to the interventions rather than participants (Oluwatosin 2000; Okeniyi 2005). The participants had multiple wounds in many cases, and some participants would have received both interventions. In this update, a trial that required participants to have two burns (Malik 2010), and a trial that may have randomised participants but appears to have reported healing by pressure injury rather than by participant (Yapucu Gunes 2007), were excluded. The data in these trials were presented by wound and thus could not be combined (if possible) with trials where data were presented by participant in both the first version of the review and this update. Such methods were not foreseen in the protocol, where it was assumed that data would be presented by participant. Randomising by wound breaches the assumption of independence that underpins inferential testing, increases the weight of a study inappropriately if included in a meta-analysis (by doubling the denominator) and thereby artificially improves the precision of the confidence interval for the summary statistic. Additionally, a trial requiring participants to have two wounds that randomises one wound to each treatment is not clinically generalisable as it has reduced between-patient variability. Between-patient variability in pragmatic trials drives external validity. The inclusion criteria have been adjusted in this update to reflect this change.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Al Waili 1999

MethodsSingle-centred, 2-armed parallel group RCT.
Participants50 participants who had had Caesarean sections or hysterectomies.
Setting: hospital.
Country: United Arab Emirates.
Inclusion criteria: acute post-operative bacterial wound infections confirmed by culture and sensitivity.
Exclusion criteria: not reported.
InterventionsGroup 1 (n = 26): Yemeni honey.
Group 2 (n = 24): 70% ethanol with povidone-iodine.
Treatment duration: not reported, dressing changed 12-hourly.
OutcomesComplete healing:
Group 1: 22/26 (84.6%);
Group 2: 12/24 (50.0%).
NotesAll participants received systemic antibiotics. The authors have not responded to requests for additional information.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “After informed consent the patients were allocated randomly into two groups”.
Comment: method of generating the random schedule not reported.
Allocation concealment (selection bias)Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Unclear risk Comment: not stated.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Comment: Table 6 shows that all the randomised participants completed follow-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Low risk Comment: ITT analysis was not reported, but, since there were no drop-outs reported, and all the randomised participants completed the study, ITT analysis was assumed to have been done and to be acceptable.  
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasLow risk Quote: “Both groups were comparable with regards to age, sex, and duration of symptoms, type and severity of bacterial infections, clinical signs and symptoms and use of systematic antibiotics”.
Comment: there was no imbalance in the baseline characteristics, and the study seemed to be free from other forms of bias.

Baghel 2009

MethodsSingle-centered, 2-arm parallel group RCT.
Participants78 participants admitted to burn unit of MY hospital Indore over a period of 2 years (June 2006-June 2008).
Setting: hospital.
Country: India.
Inclusion criteria: 10-50 years of age, with 1st- and 2nd-degree burns, burn area < 50% of TBSA.
Exclusion criteria: patients on chemotherapy, with renal and/or liver failure, immuno-compromised state and those with bronchial asthma.
InterventionsGroup 1 (n = 37): honey dressing applied daily.
Group 2 (n = 41): SSD applied daily.
Treatment duration: not reported, duration of follow-up 2 months.
Outcomes

Complete healing:
Group 1: 30/37 (81.1%);
Group 2: 15/41 (36.6%).

Mean time to healing:
Group 1: 18.1 days (No SD);
Group 2: 32.6 days (No SD).

NotesComplete healing included healing without scarring or contractures. Formation of soft scar, hypertrophic scar and/or contracture was counted as incomplete recovery. The authors have not responded to requests for additional information.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “After taking consent from the patients/parents or guardians, patients were randomly attributed into two study groups; Honey group and SSD group . . .”.
Comment: method of generation of the random sequence not reported.
Allocation concealment (selection bias)Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Unclear risk Comment: not stated.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Comment: Tables 3 and 5 showed there were no drop-outs, all the randomised participants were followed-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Low risk Comment: ITT analysis was not reported, but since no drop-outs were reported, and all the randomised participants completed the study, ITT analysis was assumed to have been done and to be acceptable.  
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasUnclear risk Comment: although the baseline characteristics were broadly similar, a greater proportion of patients treated with honey were admitted to hospital within 1-8 h of the burn (65%) compared to the SSD group (11%). The study seemed to be free from other forms of bias.

Gethin 2009

MethodsMulti-centred, 2-armed, open label RCT.
Participants108 participants recruited February 2003-January 2006.
Setting: hospital and community leg ulcer clinics.
Country: Ireland.
Inclusion criteria: > 18 years, wound area < 100 cm2, > 50% of wound covered by slough, able to provide written informed consent.
Exclusion criteria: current wound infection, medicated with antibiotics or steroids for any reason, cavity or malignant lesion.
Interventions

Group 1 (n = 54): monofloral (manuka) honey (Woundcare 18+) + compression at dose of 5 g/20 cm2 applied weekly.
Group 2 (n = 54): hydrogel (IntraSite) + compression at dose of 3 g/20 cm2 applied weekly.

Treatment duration: 4 weeks, dressing changed with compression.

OutcomesComplete healing at 12 weeks:
Group 1: 24/54 (44.4%);
Group 2: 18/54 (33.3%).
NotesHealing was a secondary outcome. The primary outcome was change in area of slough at 4 weeks (no significant difference).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk Quote: “The allocation sequence was generated using serially numbered, sealed, opaque envelopes, prior to the study by two persons independent of the study”.
Comment from study author (personal communication): the sequence was generated in two stages each of which was independent of the researcher. A number of coloured cards either treatment or controls were prepared for the total number of participants required for recruitment. These were then shuffled and placed in sealed envelopes. The sealed envelopes were then shuffled again and were sequentially numbered. This process was completed by two people who were not involved in the study.
Allocation concealment (selection bias)Low risk Quote: “patients were randomised via remote phone allocation to either treatment group”.
Comment: centrally randomised via remote phone allocation.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
High risk Quote: “This prospective, open label, 12 week, multicentre, randomised controlled trial was conducted . . .”.
Comment: open label RCT, so blinding of participants not done.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
High risk Quote: “This prospective, open label, 12 week, multicentre, randomised controlled trial was conducted . . .”.
Comment: open label RCT, so blinding of healthcare providers not done.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
High risk Quote: “Blinded outcome assessment was not possible because of obvious difference in the colour and presentation of the products, specifically orange staining of the peri-wound skin when [manuka honey] was used”.
Comment: primary outcome assessors were not blinded.
Quote: “All statistician analyses were performed using SPSS version 14 and Stata 9.2 by a statistician blinded to the treatment allocations on the intention-to-treat population”.
Quote: “The laboratory was blinded to the treatment allocation”.
Comment: Secondary outcome assessors were blinded.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Comment: Figure 1 shows that no patients were lost to follow-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Low risk Quote: “All patients were included in the final analysis”.
Comment: ITT analysis had been done, as all the randomised participants were included in the final results. 
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasLow risk Quote: “There were no statistical baseline differences between groups”.
Comment: ulcers in the honey group were larger (5.4 vs 4.2 cm2), present for longer (39.5 vs 29.9 weeks) and had a greater area covered by slough (85.5% vs 78.2%), however, these factors would affect the likelihood of healing in the honey group. The study seems to be free from other forms of bias.

Ingle 2006

MethodsSingle-centred, 2-armed, double-blind, parallel group RCT.
Participants87 participants with shallow wounds recruited September 1995-July 1996.
Setting: community.
Country: South Africa.
Inclusion criteria: patients with wounds < 2 cm deep, abrasions 10 cm2-100 cm2 (including donor sites for skin grafting and partial-thickness burns).
Exclusion criteria: patients with wounds > 100 cm2; unwilling to have an HIV test; infected wound; genital or malignant ulcers; wounds on legs, perineum, fingers or toes that would make measurement difficult; systemic disease; chronic alcoholism.
InterventionsGroup 1 (n = 40): monofloral (Aloe vera) honey applied daily.
Group 2 (n = 42): hydrogel (IntraSite) applied daily.
Treatment duration: until complete healing (abrasion) or wound < 3 cm2 (shallow wound).
OutcomesMean time to healing (all wounds) - information supplied by authors:
Group 1: 16.48 days (SD 8.40);
Group 2: 16.88 days (SD 11.31).
NotesDiet supplemented with zinc sulphate and vitamins A, B and C for all participants. 5 participants excluded from analysis after randomisation.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk Quote: “then randomised (using random permuted blocks of size 10) to treatment with either honey or IntraSite Gel”.
Comment: method of generation of random schedule reported.
Allocation concealment (selection bias)Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
Unclear risk Quote: “A prospective, randomised, double-blind controlled trial was carried out by authors . . . Patients did not know which agent was being used”.
Comment: whilst reported as double-blind, the information given was insufficient to permit judgement regarding how blinding of participants was maintained.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Quote: “A prospective, randomised, double-blind controlled trial was carried out by authors . . . Patients did not know which agent was being used”.
Comment: whilst reported as double-blind, the information given was insufficient to permit judgement as it did not state whether the healthcare providers were blinded.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Low risk Quote: “A prospective, randomised, double-blind controlled trial was carried out by authors . . . When the healing endpoint was approaching [KP] measured the surface area daily, still blinded, the applied agent from the previous day having been washed off with normal saline”.
Comment: blinding of outcome assessor judged to be adequate. 
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Quote: “Of 87 patients enrolled, 5 were excluded from the analysis . . . ”.
Comment: the loss to follow-up was less than 10%, and judged to be acceptable.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
High risk Quote: “Of 87 patients enrolled, 5 were excluded from the analysis . . .”.
Comment: ITT analysis was not done, as 5 of the 87 patients defaulted, and were not included in the results.
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasLow risk Quote: “The composition of the groups did not differ significantly in terms of recorded characteristics”.
Comment: there was no imbalance in the baseline characteristics and the study seemed to be free of other forms of bias.

Jull 2008

MethodsMulti-centred, 2-armed, parallel group RCT.
Participants368 participants with venous or mixed venous/arterial leg ulcers recruited May 2004-September 2005.
Setting: community nursing services.
Country: New Zealand.
Inclusion criteria: venous ulcer (clinical presentation + AB I > 0.8) or mixed venous/arterial ulcer (clinical presentation + ABI > 0.7), receiving compression, able to provide informed consent, residing in one of 4 study regions.
Exclusion criteria: diagnosis of diabetes, rheumatoid arthritis or significant peripheral arterial disease, allergy to honey or calcium alginate, currently using honey treatment.
Interventions

Group 1 (n = 187): monofloral (manuka) honey-impregnated calcium alginate dressing (ApiNate) + compression bandaging system normally available at study centre.
Group 2 (n = 181): usual care: choice of any dressing clinically indicated + compression system normally available at study centre.

Treatment duration: until healing or 12 weeks, dressing changed with compression.

OutcomesComplete healing at 12 weeks:
Group 1: 104/187 (55.6%);
Group 2: 90/181 (49.7%).
NotesNo difference between groups for time to healing, change in ulcer area, incidence of infection or health-related quality of life.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk Quote: “The allocation sequence was stratified by study centre and Margolis index using minimization”.
Comment: sequence generated using minimization technique.
Allocation concealment (selection bias)Low risk Quote: “Participants were randomly assigned to one of two groups by an independent central telephone service”.
Comment: allocation concealed using an independent central telephone service.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
High risk Quote: “open-label, multicentre randomised controlled trial was conducted”.
Comment: open label RCT, so blinding of participants not done.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
High risk Quote: “open-label, multicentre randomised controlled trial was conducted”.
Comment: open label RCT, so blinding of healthcare providers not done.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
High risk

Quote: “The primary outcome measure was the proportion of participants with completely healed reference ulcers at 12 weeks, as determined by the research nurse. The research nurse was not blind to allocation”.

Comment: primary outcome assessor not blinded.

Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Quote: “Loss to follow-up was similar between the two groups, although withdrawal from the study differed significantly (31 participants in the honey-treated group compared with none in the usual care group) . . . All participants who withdrew were followed up at 12 weeks”.
Comment: outcome data was collected for all participants unless lost to follow-up. 6 participants (< 2%) were lost to follow-up, all in the control group. The loss to follow-up was < 10% and judged to be acceptable.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Low risk Quote: “The primary analysis was by intention to treat, with all participants included, and participants lost to follow-up deemed treatment failures”.
Comment: ITT analysis was done, as all the randomised participants were included in the final results. 
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results. The trial was registered in a publicly available trials register (ISRCTN06161544).
Other biasLow risk Quote: “Baseline data were similar for both study groups”.
Comment: there was no imbalance in the baseline characteristics and the study seemed to be free from other forms of bias.

Marshall 2005

MethodsSingle-centred, 2-armed, single-blind, parallel group RCT.
Participants51 participants.
Setting: outpatient clinic.
Country: England.
Inclusion criteria: patients suitable for toenail removal (unilateral or bilateral, partial or total) with matrix phenolisation.
Exclusion criteria: unable to give informed consent, unable to attend follow-up clinics, peripheral vascular disease, peripheral neuropathy.
InterventionsGroup 1 (n = 27): monofloral (jarrah) honey dressing daily.
Group 2 (n = 24): iodine (Inadine) dressing daily.
Treatment duration: until complete epithelialisation of nail bed.
OutcomesMean time to healing:
Group 1: 33.4 days (SD 15.71);
Group 2: 25.3 days (SD 8.70).
NotesImbalance in numbers of diabetics in honey group compared to comparison treatment (9 vs 4) and in total avulsions (16 vs 7) both of which favoured the comparison treatment.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk Quote: “random tables were used to determine group allocation”.
Comment: method of generation of random schedule reported.
Allocation concealment (selection bias)Low risk Quote: “Those given written informed consent were randomly assigned to the intervention groups by telephone randomisation. This involved a phone call to an independent assistant located outside of the clinical settings with no prior knowledge of the participants”.
Comment: allocation concealed using an independent central telephone service.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
High risk Quote: “The study was single blind trial. While the operating clinician and the patients could not be blinded to the intervention . . .”.
Comment: blinding of participants not done.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
High risk Quote: “The study was single blind trial. While the operating clinician and the patients could not be blinded to the intervention . . .”.
Comment: blinding of healthcare providers not done.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Low risk Quote: “ . . . the outcome assessor was unaware of group allocation”.
Comment: blinding of outcome assessors was done, and it was unlikely that the blinding could have been broken.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
High risk Quote: “A total of 7/51 participants withdrew from the trial: 4/27 in the honey group, of which 2/4 were lost to follow up and 2/4 were withdrawn due to non-compliance. In the iodine group, 3/24 withdrew from the trial; 1/3 lost to follow up, 1/3 withdrawn for non-compliance, and 1/3 required further surgical intervention.”
Comment: reasons for drop-outs were given, but the rate was > 10%, and judged to be unacceptable.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
High risk Quote: “All the seven participants were excluded from the primary analysis.”
Comment: ITT analysis not done, as the randomised participants were not all included in the final analyses.
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasHigh risk Quote: “In respect of prognostic factors randomisation allocated more patients who smoked (7 vs 3), and more patients with diabetes (9 vs 4) to the honey group”.
Comment: there was baseline imbalance with respect to demographics, as more participants who smoked and had diabetes were allocated to the honey group.

Mashood 2006

MethodsSingle-centered, 2-armed, parallel group RCT.
Participants50 participants recruited September 2002-August 2003.
Setting: hospital.
Country: Pakistan.
Inclusion criteria: patients of all ages who sustained superficial and partial-thickness burns of < 15% TBSA, and with no co-morbidities present.
Exclusion criteria: patients with deep burns and those who sustained burns of > 15% TBSA, whether was superficial or deep.
InterventionsGroup 1 (n = 25): honey.
Group 2 (n = 25): 1% SSD.
Treatment until healed.
Duration of follow-up: 6 months.
OutcomesComplete healing in weeks:
Group 1: 2 weeks = 13/25, 4 weeks = 25/25;
Group 2: 2 weeks = 5/25, 4 weeks = 15/25, 6 weeks = 25/25.
NotesPatients with deep partial-thickness burns were included. The authors have not responded to requests for additional information.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “They were randomly assigned to two groups. Each group contained 25 patients”.
Comment: method of generating the random sequence not reported.
Allocation concealment (selection bias)Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Unclear risk Comment: not stated.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Comment: Tables 1 and 2 show that there were no drop-outs; all the randomised participants were followed-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Low risk Comment: ITT analysis was not reported, but since no drop-outs were reported, and all the randomised participants completed the study, ITT analysis was assumed to have been done and to be acceptable.  
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasUnclear risk Comment: the baseline characteristics were not reported, so there was insufficient information to judge whether any other important form of bias existed.

McIntosh 2006

MethodsSingle-centred, 2-armed, double-blind, parallel group RCT.
Participants100 participants.
Setting: outpatient clinic.
Country: England.
Inclusion criteria: patients suitable for toenail surgery (unilateral or bilateral, partial or total) with matrix phenolisation.
Exclusion criteria: age < 16 years, unable to give informed consent, unable to attend follow-up clinics, communication barriers, unsuitable for toenail surgery (patients with peripheral vascular disease, unstable diabetes, or where local anaesthetic was contra-indicated).
Interventions

Group 1 (n = 52): monofloral (manuka) honey-impregnated calcium alginate (ApiNate) twice weekly.
Group 2 (n = 48): paraffin-impregnated gauze (Jelonet), twice weekly.

Treatment duration: until healed.

OutcomesMean time to healing:
Group 1: 40.30 days (SD 18.21);
Group 2: 39.98 days (SD 25.42).
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk Quote: “Random tables were used to determine intervention allocation”.
Comment: method of generation of random schedule reported.
Allocation concealment (selection bias)Low risk Quote: “Participants were assigned to intervention groups by remote randomisation. This involved a telephone call to an independent assistant located outside of the study setting who had no prior knowledge of the participants”.
Comment: allocation concealed using an independent central telephone service.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
Low risk Quote: “This was a double blind study. Both the outcomes assessors and participants were blind to the intervention throughout. Removal and application of all dressings were performed in a treatment group with only the investigator and participant present; a screen concealed the participant’s feet during dressing removal and application”.
Comment: blinding of participants was done.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
High risk Quote: “Removal and application of all dressings were performed in a treatment group with only the investigator and participant present”.
Comment: blinding of healthcare providers not done.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Low risk Quote: “This was a double blind study. Both the outcomes assessors and participants were blind to the intervention throughout ... All evidence of the intervention was removed and wounds were irrigated before the outcome assessors entered the room”.
Comment: blinding of outcome assessors was done.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
High risk Quote: “A total of 13/100 participants withdrew from the trial: 5/52 from the honey group (one was lost to follow-up and four withdrew because of non-concordance) and 8/48 from the paraffin tulle gras group (five were lost to follow-up and three withdrew due to non-concordance)".
Comment: Reasons for drop-outs were given, but the rate was more than 10% and judged to be unacceptable.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
High risk Quote: “All 13 withdrawals were excluded from primary analyses”.
Comment: ITT analysis not done, as not all the randomised participants were included in the final analyses.
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasHigh risk Quote: “There were disparities in baseline demographics. Established prognostic factors differed between groups: more smokers were assigned to the paraffin tulle gras group, and more diabetics to the honey group.”.
Comment: whilst the study report stated that there were more smokers assigned to the paraffin tulle gras group, the data in table 1 (baseline demographics) stated that more smokers were assigned to the honey group.

Memon 2005

MethodsSingle-centred, 2-armed, parallel group RCT.
Participants80 participants with superficial-dermal, mid-dermal or deep-dermal burns recruited January 2002-December 2003.
Setting: hospital.
Country: Pakistan.
Inclusion criteria: age 4-62 years, TBSA burnt 10-40%.
Exclusion criteria: patients with chemical or electrical burns, full-thickness burns or burns involving > 40% TBSA.
Interventions

Group 1 (n = 40): natural, unprocessed honey-gauze dressings every other day.

Group 2 (n = 40): SSD-gauze dressings every other day.
Treatment duration: not reported.
Follow-up duration: until healed.

OutcomesNumber healed:
Group 1: by day 16 (n = 20), by day 26 (n = 12), by day 30 (n = 8). Mean 15.3 days (no SD).
Group 2: by day 20 (n = 16), by day 36 (n = 18), by day 46 (n = 6). Mean 20.0 days (no SD).
NotesThe authors have not responded to requests for additional information.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “The patients were allotted at random in two different groups”.
Comment: in addition, it was reported in the abstract that the design was "a quasi-experimental study". The method for generating the random sequence was not reported.
Allocation concealment (selection bias)Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Unclear risk Comment: not stated.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Comment: Tables 4 and 5 showed there were no drop-outs; all the randomised participants were followed-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Low risk Comment: ITT analysis was not reported, but since no drop-outs were reported and all the randomised participants completed the study, ITT analysis was assumed to have been done and to be acceptable.   
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasHigh risk Comment: there was a baseline imbalance in demographics such as % TBSA and depth of burn. More participants with burns 16-25% TBSA were randomised to the SSD group (20 vs 14). The honey group had more participants with burns 10-15% TBSA (18 vs 12). More participants in the SSD group had deep-dermal burns (20 vs 16), whereas more participants in the honey group had superficial-dermal burns (18 vs 12).

Mphande 2007

MethodsSingle-centred, 2-armed, quasi-randomised controlled trial.
Participants40 participants with open or infected wounds (chronic osteomyelitis n = 7, post-surgical n = 14, ulcer n = 8, trauma n = 9, abscess n = 2) recruited February-November 2005.
Setting: hospital with outpatient follow-up.
Country: Malawi.
Inclusion criteria: not reported.
Exclusion criteria: lived too far from hospital for follow-up.
InterventionsGroup 1 (n = 22): honey-soaked gauze daily; frequency reduced after 1 week if wound healing progressing.
Group 2 (n = 18): sugar covered with gauze dressing; frequency reduced after 1 week if wound healing progressing.
Treatment duration: not reported.
Follow up duration: not reported.
OutcomesMedian time to complete healing:
Group 1: 31.5 days (no SD);
Group 2: 56.0 days (no SD).
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High risk Quote: “Patients were randomised to receive a honey or sugar dressing. They were allocated to one of the two groups on an alternating basis at admission”.
Comment: method of generating sequence was not random and, therefore, not adequate.
Allocation concealment (selection bias)High risk Quote: “They were allocated to one of the two groups on an alternating basis at admission”.
Comment: allocation was judged to have been inadequately concealed, as alternation was used.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Unclear risk Comment: not stated.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Unclear risk Comment: the study did not state whether there were any drop-outs, or whether all the randomised participants were followed-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Unclear risk Comment: no drop outs or withdrawals were reported. The total numbers of participants assessed were also not reported. We cannot judge whether an ITT analysis was conducted.
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasUnclear risk Quote: “The honey group comprised 22 patients (13 males and nine females) with a mean age of 12.7 years (range 1–39). The sugar group comprised 18 patients (12 males and six females) with a mean age of 13.8 years (range 3–53).There was a range of causes of wounds, but their distribution was similar between the two groups.”.
Comment: age, sex and types of wounds similar between the two groups, but no information was reported on other baseline characteristics.

Nilforoushzadeh 2007

MethodsSingle-centred, 2-armed, parallel group RCT.
Participants100 participants with confirmed cutaneous Leishmaniasis.
Setting: skin disease and Leishmaniasis research centre.
Country: Iran.
Inclusion criteria: patients with confirmed cutaneous Leishmaniasis with direct smear, no history of systemic or topical therapy for cutaneous Leishmaniasis, absence of malnutrition or severe predisposing disease such as cardiac, renal or hepatic disease and other contraindication for glucantime.
Exclusion criteria: pregnant and lactating women, lesions < 3 months old, and patients treated with drugs that interact with glucantime.
InterventionsGroup 1 (n = 45): intralesional injection of meglumine antimoniate (glucantamine) once weekly and dressed with honey-soaked gauze twice daily.
Group 2 (n = 45): intralesional injection of meglumine antimoniate (glucantamine) once weekly.
Treatment duration:until complete healing of wounds, or maximum 6 weeks.
Outcomes

Complete healing:
Group 1: 23/45 (51.1%);
Group 2: 32/45 (71.1%).

Mean time to healing in days:
Group 1: 7.04 (± 3.09);
Group 2 : 6.30 (± 2.29).

NotesThis RCT reported that, initially, 100 patients were confirmed with cutaneous Leishmaniasis and were randomised into two groups. Further on, in the results section, the authors report that each group had 45 patients and stated that 10 patients left the study. They also reported that 23 patients in the honey-treated group achieved complete cure, whilst in the glucantime alone group 32 patients achieved complete cure. 13 patients from the honey-treated group left the study, as did 10 patients from the glucantime group.     
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk Quote: “The patients were randomised into 2 groups, using Random allocation software. (version 1.0, may 2004; Saghaei)”.
Comment: method of generation of random sequence reported.
Allocation concealment (selection bias)Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Low risk Quote: “Diameter of the lesion and size of the erythema, induration and ulcer were measured by use of the millimetre papers. These evaluations performed [sic] by the investigators who were blinded to the type of treatment”.
Comment: blinding of outcome assessors was done.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
High risk Quote: "Overall, in the topical honey treated group, 13 patients left out [sic] the study. One patient (7.7%) left out the study because of contact dermatitis to honey and 12 patients left out of the study because of progression of their lesions. In the glucantime treated group, 10 patients left out [sic] the study because of progression of their lesions".
Comment: reasons for drop-outs provided, but the rate was > 10%, and judged to be unacceptable.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
High risk Comment: the study stated that 100 participants were randomised, but there were only 45 included in each arm (see table 1 baseline demography). Percentages were inaccurate because the denominators used were 45.
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasUnclear risk Comment: age, sex, number and location of lesions similar between the two groups, but no information reported on potentially prognostic baseline characteristics, such as size of lesions.

Robson 2009

MethodsSingle-centred, parallel group, open-label RCT.
Participants105 participants recruited September 2004-May 2007.
Setting: large district hospital.
Country: United Kingdom.
Inclusion criteria: patients with a wound healing by secondary intention.
Exclusion criteria: patients with: diabetes, history of neuroses, psychoses or dementia, known allergy to bee/honey products, venous ulcers of < 12 week duration, Grade 1 or Grade 4 pressure ulcers (EPUAP grades), wounds containing exposed tendon, muscle or bone, or wounds where malignancy was present or suspected; patients with an existing wound infection requiring systemic antibiotics and those who had received antibiotic therapy in the preceding 2 weeks.
InterventionsGroup 1 (n = 52): manuka honey.
Group 2 (n = 53): conventional treatment.
Duration of treatment 24 weeks.
Outcomes

Healing rate at 24 weeks:

Group 1: 72.7%;

Group 2: 63.3%.

Healing rate at 12 weeks:

Group 1: 46.2%;

Group 2: 34.0%.

Median time to heal:
Group 1: 100 days;

Group 2: 140 days.

Time to heal in days (Time to event):
Group 1: 0 days = 50, 50 days = 30, 100 days = 20, 150 days = 12, 200 days = 1.
Group 2: 0 days = 51, 50 days = 36, 100 days = 25, 150 days = 15, 200 days = 1.

Notes52 patients were randomized to receive honey and 53 to receive conventional treatment. 2 patients randomized to the honey group (3.8%) did not receive honey (1 as a result of the patient’s decision, 1 as a result of a clinical decision), and 6 allocated to the conventional treatment group (11.3%) received honey (all except 1 as a result of a clinician’s decision).
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk Quote: “Allocation to treatment was determined using blocked randomisation (with sequence produced using computer software (STATA version 8.2; StataCorp, College \station, TX, USA) with randomly varying block size), stratified by two factors, age (< 40 and ≥ 40 year old) and size of wound (< 10 and ≥ 10 cm2)”.
Comment: method of generation of random schedule reported.
Allocation concealment (selection bias)Low risk Quote: “Sealed, opaque, serially numbered envelopes were produced from the randomisation sequence for each stratum separately, and an independent third party with access to the envelopes was contacted by telephone to determine treatment allocation as patients were recruited”.
Comment: allocation concealed using sealed, opaque, serially numbered envelopes and an independent central telephone service.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
High risk Quote: “The study was designed as a single centre, open-label, randomized controlled trial”.
Comment: open label RCT, so blinding of participants not done.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
High risk Quote: “The study was designed as a single centre, open-label, randomized controlled trial”.
Comment: open label RCT, so blinding of healthcare providers not done.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
High risk Quote: “The study was designed as a single centre, open-label, randomized controlled trial”.
Comment: open label RCT, so blinding of outcome assessors not done.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Quote: “One patient in the honey group (1.9%) was lost to follow up (as they moved to an alternative hospital) and one patient died in each group (1.9% in each group)”.
Comment: drop-out rate < 10%, and judged to be acceptable.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Low risk Quote: “Statistical analysis was carried out on an intention to treat (ITT) basis, retaining patients in their randomised treatment groups regardless of the actual treatment received and including protocol violators and ineligible patients”.
Comment: ITT analysis was done, as all the randomised participants were included in the final results.
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasLow risk Comment: there was no imbalance in the baseline characteristics, and the study seemed to be free from other forms of bias.

Shukrimi 2008

MethodsSingle-centered, 2-armed, parallel group RCT.
Participants30 participants.
Setting: hospital.
Country: Malaysia.
Inclusion criteria: all non-Insulin dependent diabetes mellitus patients (NIDDM) with Wagner grade II ulcers who were admitted for surgery were enrolled if the following parameters were met: age 35-65, transcutaneous oxygen tension > 30 mmHg and serum albumin level of > 35 g/dl.
Exclusion criteria: multiple medical co-morbidity, steroid therapy, neutrophil count < 2000/mm3.
InterventionsGroup 1: honey applied daily.
Group 2: povidone-soaked gauze applied daily.
Duration: until wound closure.
OutcomesMean time to heal in days:
Group 1: 14.4 (no SD);
Group 2: 15.4 (no SD).
NotesThe study did not state the number of participants randomised to each arm, or the percentage of wounds healed in each group.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “The patients were randomised to two dressing arms; honey dressing group and standard dressing group”.
Comment: method of generating the random schedule not reported.
Allocation concealment (selection bias)Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Low risk Quote: “All the wounds were assessed every other day by a surgeon blinded to the material of dressing”.
Comment: blinding of outcome assessors was done and it was unlikely that the blinding could have been broken.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Unclear risk Comment: the study did not report the numbers allocated to each treatment, drop-outs, or state whether all the randomised participants were followed-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Unclear risk Comment: the study did not report the numbers allocated to each treatment, drop-outs or withdrawals. The total numbers of participants assessed were not reported either. We cannot judge whether an ITT analysis was conducted.
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasUnclear risk Comment: the baseline characteristics were not reported, so there was insufficient information to judge whether any important form of bias existed.

Subrahmanyam 1991

MethodsSingle-centred, 2-armed, parallel group RCT.
Participants104 participants with burns < 40% TBSA recruited July 1988-December 1989.
Setting: hospital.
Country: India.
Inclusion criteria: superficial burns.
Exclusion criteria: not reported.
InterventionsGroup 1 (n = 52): unprocessed, undiluted honey dressings daily.
Group 2 (n = 52): SSD-impregnated gauze daily.
Treatment duration: until healed.
OutcomesMean time to healing:
Group 1: 9.4 days (SD 2.3);
Group 2: 17.2 days (SD 3.2).
NotesInformation on allocation method, allocation concealment, blinding, mean time to healing and standard deviation for mean time to healing were provided by the author.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “The cases were allocated at random to two groups”.
Comment: method of generating random sequence not reported. Author provided information that the sequence was generated by the "chit method", but it is not clear how this method works.
Allocation concealment (selection bias)Unclear risk Comment: not stated, but author provided information that allocation concealment was by means of sequentially-numbered, sealed envelopes, although it is not clear whether the envelopes were opaque.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
High risk Comment: not stated in study report, but author responded to request for further information by stating the patients were not blinded.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded. How blinding was achieved was not described in the response.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Comment: Table 2 showed there were no drop-outs, and that all the randomised participants were followed-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Low risk Comment: ITT analysis was not reported, but since no drop-outs were reported, and all the randomised participants completed the study, ITT analysis was assumed to have been done and to be acceptable.  
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasLow risk Comment: there was no imbalance in baseline characteristics, and the study seemed to be free from other forms of bias.

Subrahmanyam 1993a

MethodsSingle-centred, 2-armed, parallel group RCT.
Participants

92 participants with burns < 40% TBSA recruited January 1990-January 1991.
Setting: hospital.

Country: India.
Inclusion criteria: treated within 6 h of injury, partial-thickness burns.
Exclusion criteria: not reported.

InterventionsGroup 1 (n = 46): unprocessed, undiluted, honey-impregnated gauze daily.
Group 2 (n = 46): polyurethane film (OpSite) left intact until day 8, unless evidence of infection, excessive exudate or leakage.
Treatment duration: until healed.
OutcomesMean time to healing:
Group 1: 10.8 days (SD 3.93);
Group 2: 15.3 days (SD 2.98).
NotesInformation on allocation method, allocation concealment, blinding, mean time to healing and standard deviation for mean time to healing provided by author.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “After initial management, patients were allotted at random to two groups”.
Comment: method of generation of random sequence not reported. Author informed us that the sequence was generated by the "chit method", but it is not clear what this method is.
Allocation concealment (selection bias)Unclear risk Comment: not stated, but author provided information that allocation concealment was via sequentially-numbered sealed envelopes, although it is not clear whether the envelopes were opaque.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
High risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded, but not patients.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded. How blinding was achieved was not described in the response.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Comment: Table 1 showed that there were no drop-outs, and that all the randomised participants were followed-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Low risk Comment: ITT analysis was not reported, but since no drop-outs were reported, and all the randomised participants completed the study, ITT analysis was assumed to have been done and to be acceptable.  
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasUnclear risk Comment: the baseline characteristics were not reported, so there was insufficient information available to judge whether any important form of bias existed.

Subrahmanyam 1993b

MethodsSingle-centred, 2-armed, parallel group RCT.
Participants100 participants with burns or ulcers recruited January 1989-January 1990.
Setting: hospital.
Country: India.
Inclusion criteria: not reported.
Exclusion criteria: not reported.
InterventionsGroup 1 (n = 50): unprocessed, undiluted, honey-impregnated gauze daily.
Group 2 (n = 50): SSD-impregnated gauze daily.
Treatment duration: until healed.
OutcomesMean time to healing:
Group 1: 9.5 days (SD 6.2);
Group 2: 22.5 days (SD 5.2).
NotesInformation on allocation method, allocation concealment, blinding, mean time to healing and standard deviation for mean time to healing provided by author.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “Patients were divided into two groups and they were distributed at random”.
Comment: method of generating random sequence was not reported. Author provided information that the sequence was generated by the "chit method", but it is not clear what this method is.
Allocation concealment (selection bias)Unclear risk Comment: not stated, but author provided information that allocation concealment was by means of sequentially-numbered, sealed envelopes, although it is not clear whether the envelopes were opaque.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
High risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded. How blinding was achieved was not described in the response.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded. How blinding was achieved was not described in the response.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded. How blinding was achieved was not described in the response.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Comment: Table 3 showed there were no drop-outs, and that all the randomised participants were followed-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Low risk Comment: ITT analysis was not reported, but since no drop-outs were reported, and all the randomised participants completed the study, ITT analysis was assumed to have been done and to be acceptable.  
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasUnclear risk Comment: there was no baseline imbalance with respect to patients' age between two groups, however, other baseline characteristics were not reported, so there was insufficient information to judge whether any important form of bias existed.

Subrahmanyam 1994

MethodsSingle-centred, 2-armed, parallel group RCT.
Participants100 participants with partial-thickness burns recruited June 1991-July 1992.
Setting: hospital.
Country: India.
Inclusion criteria: treated within 6 h of injury, TBSA burnt < 40%.
Exclusion criteria: not reported.
InterventionsGroup 1 (n = 50): unprocessed, undiluted, honey-impregnated gauze changed every 2nd day.
Group 2 (n = 50): amniotic membrane left intact until day 8, and then changed every 2nd day.
Treatment duration: until healed.
OutcomesMean time to healing:
Group 1: 9.4 days (SD 2.52);
Group 2: 17.5 days (SD 6.66).
NotesInformation about allocation method, allocation concealment, blinding, and standard deviation for mean time to healing provided by author.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “After initial treatment, patients were allotted to two groups at random”.
Comment: method of generating the random sequence not reported. Author provided information that the sequence was generated by the "chit method", but it is not clear what this method is.
Allocation concealment (selection bias)Unclear risk Comment: not stated, but author provided information that allocation concealment was by means of sequentially-numbered, sealed envelopes, although it is not clear whether the envelopes were opaque.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
High risk Comment: not stated in study report, but author responded to request for further information by stating the patients were not blinded.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded. How blinding was achieved was not described in the response.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Comment: Tables 2 and 3 show that there were no drop-outs, all the randomised participants were followed-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Low risk Comment: ITT analysis was not reported, but since no drop-outs were reported, and all the randomised participants completed the study, ITT analysis was assumed to have been done and to be acceptable.  
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasLow risk Comment: there was no imbalance in the baseline characteristics, and the study seemed to be free from other forms of bias.

Subrahmanyam 1996a

MethodsSingle-centred, 2-armed, parallel group RCT.
Participants900 participants with partial-thickness burns recruited July 1987-December 1993.
Setting: hospital.
Country: India.
Inclusion criteria: TBSA burnt < 40%.
Exclusion criteria: not reported.
InterventionsGroup 1 (n = 450): pure, unprocessed, undiluted, honey-impregnated gauze every 2nd day.
Group 2 (n = 450): Soframycin (90 participants), Vaseline-impregnated gauze (90 participants), OpSite (90 participants), sterile gauze (90 participants) or left exposed (90 participants). "Dressings were replaced on alternative days, except in the case of OpSite, which was continued until the wounds healed... sterile linen changed at frequent intervals." Frequency of dressing change is not mentioned with respect to the sterile gauze group.
Treatment duration: until healed.
OutcomesMean time to healing:
Group 1: 8.8 days (SD 2.1);
Group 2: 13.5 days (SD 4.1).
NotesInformation about allocation method, allocation concealment, blinding, and standard deviation for mean time to healing provided by author.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “After initial treatment, the cases were divided at random into a study group treated with honey dressing and a control group treated with conventional dressing”.
Comment: method of generating the random sequence not reported. Author provided information that the sequence was generated by the "chit method", but it is not clear what this method is.
Allocation concealment (selection bias)Unclear risk Comment: not stated, but author provided information that allocation concealment was by means of sequentially-numbered, sealed envelopes, although it is not clear whether the envelopes were opaque.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
High risk Comment: not stated in study report, but author responded to request for further information by stating the patients were not blinded.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded. How blinding was achieved was not described in the response.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Comment: Table 1 showed that there were no drop-outs; all the randomised participants were followed-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Low risk Comment: ITT analysis was not reported, but since no drop-outs were reported, and all the randomised participants completed the study, ITT analysis was assumed to have been done and to be acceptable.  
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasUnclear risk Comment: the baseline characteristics were not reported, so there was insufficient information to judge whether any important form of bias existed.

Subrahmanyam 1996b

MethodsSingle-centred, 2-armed, parallel group RCT.
Participants

100 participants with partial-thickness burns recruited July 1992-December 1993.
Setting: hospital.

Country: India.
Inclusion criteria: treated within 6 h of injury, TBSA burnt < 40%.
Exclusion criteria: not reported.

InterventionsGroup 1 (n = 50): pure, unprocessed, undiluted honey every 2nd day.
Group 2 (n = 50): potato peel bandages every 2nd day.
Treatment duration: until healed.
OutcomesMean time to healing:
Group 1: 10.4 days (SD 2.2);
Group 2: 16.2 days (SD 2.3).
NotesInformation about allocation method, allocation concealment, blinding, and standard deviation for mean time to healing provided by author.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “After initial management, patients were allotted at random to two groups”.
Comment: method of generating the random sequence not reported. Author provided information that the sequence was generated by the "chit method", but it is not clear what this method is.
Allocation concealment (selection bias)Unclear risk Comment: not stated, but author provided information that allocation concealment was by means of sequentially-numbered sealed envelopes, although it is not clear whether the envelopes were opaque.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
High risk Comment: not stated in study report, but author responded to request for further information by stating the patients were not blinded.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded. How blinding was achieved was not described in the response.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Comment: Table 1 showed that there were no drop-outs; all randomised participants were followed-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Low risk Comment: ITT analysis was not reported, but since no drop-outs were reported, and all randomised participants completed the study, ITT analysis was assumed to have been done and to be acceptable.  
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasLow risk Comment: there was no imbalance in the baseline characteristics, and the study seemed to be free from other forms of bias.

Subrahmanyam 1996c

MethodsSingle-centred, 2-armed, blinded, parallel group RCT.
Participants

84 participants with partial-thickness burns recruited January 1993-June 1994.
Setting: hospital.

Country: India.
Inclusion criteria: treated within 6 h of injury, TBSA burnt < 40%.
Exclusion criteria: not reported.

InterventionsGroup 1 (n = 42): pure, unprocessed, undiluted honey changed every 2nd day.
Group 2 (n = 42): pure, unprocessed, undiluted honey with added vitamins C and E, and polyethylene glycol 4000 changed every 2nd day.
Treatment duration: until healed.
OutcomesMean time to healing:
Group 1: 8.3 days (SD 2.4);
Group 2: 6.4 days (SD 3.6).
NotesInformation about allocation method, allocation concealment, blinding and standard deviation for mean time to healing provided by author.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “After initial management, patients were allotted at random to two groups”.
Comment: method of generation of random sequence not reported. Author provided information that the sequence was generated by the "chit method", but it is not clear what this method is.
Allocation concealment (selection bias)Unclear risk Comment: not stated, but author provided information that allocation concealment was by means of sequentially-numbered sealed envelopes, although it is not clear whether the envelopes were opaque.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
High risk Comment: not stated in study report, but author responded to request for further information by stating the patients were not blinded.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded. How blinding was achieved was not described in the response.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Comment: Table 2 showed that there were no drop-outs; all randomised participants were followed-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Low risk Comment: ITT analysis was not reported, but since no drop-outs were reported, and all randomised participants completed the study, ITT analysis was assumed to have been done and to be acceptable.  
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasLow risk Comment: there was no imbalance in the baseline characteristics, and the study seemed to be free from other forms of bias.

Subrahmanyam 1998

MethodsSingle-centred, 2-armed, parallel group RCT.
Participants

50 participants with superficial thermal burns recruited June 1995-December 1996.
Setting: hospital.

Country: India.
Inclusion criteria: present within 6 h of injury, TBSA burnt < 40%.
Exclusion criteria: not reported.

InterventionsGroup 1 (n = 25): pure, unprocessed, undiluted honey every 2nd day.
Group 2 (n = 25): SSD-impregnated gauze daily.
Treatment duration: until healed.
OutcomesMean time to healing:
Group 1: 4.92 days (SD 3.61);
Group 2: 8.22 days (SD 8.31).
NotesInformation about allocation method, allocation concealment, blinding, mean time to healing and standard deviation for mean time to healing provided by author.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “After initial management, patients were allotted at random to two groups”.
Comment: method of generation of random sequence not reported. Author provided information that the sequence was generated by the "chit method", but it is not clear what this method is.
Allocation concealment (selection bias)Unclear risk Comment: not stated, but author provided information that allocation concealment was by means of sequentially-numbered sealed envelopes, although it is not clear whether the envelopes were opaque.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
High risk Comment: not stated in study report, but author responded to request for further information by stating the patients were not blinded.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded. How blinding was achieved was not described in the response.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Comment: Table 2 showed that there were no drop-outs; all randomised participants were followed-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Low risk Comment: ITT analysis not reported, but since no drop-outs were reported, and all randomised participants completed the study, ITT analysis was assumed to have been done and to be acceptable.  
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasLow risk Comment: there was no imbalance in the baseline characteristics, and the study seemed to be free from other forms of bias.

Subrahmanyam 1999

MethodsSingle-centred, 2-armed, parallel group RCT.
Participants

50 participants with mixed-depth (partial- and full-thickness) burns recruited January 1996-December 1997.
Setting: hospital.

Country: India.
Inclusion criteria: aged 10-40 years, haemodynamically stable, no systemic illness or smoke inhalation injury, TBSA burnt < 30%.
Exclusion criteria: not reported.

InterventionsGroup 1 (n = 25): unprocessed honey every 2nd day, with autologous skin grafting as required.
Group 2 (n = 25): early tangential excision and skin grafting 3-6 days after admission.
Treatment duration: until healed.
OutcomesMean time to healing:
Group 1: 32.0 days (SD 8.1);
Group 2: 18.4 days (SD 4.2).
NotesInformation about allocation method, allocation concealment, blinding, mean time to healing and standard deviation for mean time to healing provided by author.
3 participants in the honey-treated group died, and 1 in the early tangential excision group.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “Twenty five patients were randomly assigned to the TE group”.
Comment: method of generation of the random sequence was not reported. Author provided information that the sequence was generated by the "chit method", but it is not clear what this method is.
Allocation concealment (selection bias)Unclear risk Comment: not stated, but author provided information that allocation concealment was by means of sequentially-numbered sealed envelopes, although it is not clear whether the envelopes were opaque.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
High risk Comment: not stated in study report, but author responded to request for further information by stating the patients were not blinded.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded. How blinding was achieved was not described in the response.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Quote: “One TE patient died, from status asthaticus, while 3 HT patients died with septicaemia”.
Comment: overall the number of drop-outs was < 10%, however, drop-outs were due to death, which is of some concern given that the burns were described as “moderate”.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Unclear risk Comment: the study did not state whether all the randomised participants were followed-up and included in the final analysis, hence, we cannot judge if an ITT analysis was conducted.
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasUnclear risk Comment: the baseline characteristics were not reported, so there was insufficient information available to judge whether any important form of bias existed.

Subrahmanyam 2001a

MethodsSingle-centred, 2-armed, parallel group RCT.
Participants

100 participants with mixed-depth (partial- and full-thickness) burns recruited June 1998-December 1999.
Setting: hospital.

Country: India.
Inclusion criteria: treated within 6 h of injury, TBSA burnt < 40%.
Exclusion criteria: not reported.

InterventionsGroup 1 (n = 50): unprocessed, undiluted, monofloral (Jambhul) honey every 2nd day.
Group 2 (n = 50): SSD-impregnated gauze every 2nd day.
Treatment duration: until healed.
OutcomesMean time to healing:
Group 1: 15.4 days (SD 3.2);
Group 2: 17.2 days (SD 4.3).
NotesInformation about allocation method, allocation concealment, blinding, and standard deviation for mean time to healing provided by author.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “The patients were allocated at random to two groups, the initial management being the same”.
Comment: method of generation of random sequence not reported. Author provided information that the sequence was generated by the "chit method", but it is not clear what this method is.
Allocation concealment (selection bias)Unclear risk Comment: not stated, but author provided information that allocation concealment was by means of sequentially-numbered sealed envelopes, although it is not clear whether the envelopes were opaque.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
High risk Comment: not stated in study report, but author responded to request for further information by stating the patients were not blinded.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Unclear risk Comment: not stated in study report, but author responded to request for further information by stating the investigators and outcome assessors were blinded. How blinding was achieved was not described in the response.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Quote: “Thus, all the patients in this group, the wound healed by day 21” (patients treated with honey).
Quote:  “In the group treated with sulphur sulphadiazine, the wounds healed in 4 patients by day 7, in 22 patients by 14 day, and in 24 patients by day 21”.
Comment: no drop-outs, as all the participants randomised were followed-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Low risk Comment: ITT analysis was not reported, but since no drop-outs were reported, and all the randomised participants completed the study, ITT analysis was assumed to have been done and to be acceptable.  
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasLow risk Comment: there was no imbalance in the baseline characteristics, and the study seemed to be free from other forms of bias.

Subrahmanyam 2004

MethodsSingle-centred, 2-armed, blinded (outcome assessor), parallel group RCT.
Participants

30 consecutive males with Fournier's gangrene recruited April 2001-May 2003.
Setting: hospital.

Country: India.
Inclusion criteria: not reported.
Exclusion criteria: not reported.

InterventionsGroup 1 (n = 14): unprocessed, undiluted, monofloral (Jamun) honey daily.
Group 2 (n = 16): Edinburgh Solution of Lime- (EUSOL) soaked gauze daily.
Treatment duration: until healed.
OutcomesMean time to healing:
Group 1: 18.5 days (SD 2.1);
Group 2: 26.5 days (SD 3.2).
NotesInformation about allocation method, allocation concealment, blinding, mean time to healing and standard deviation for mean time to healing provided by author.
3 participants died: 1 in the honey-treated group and 2 in the EUSOL-treated group.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “For assessing the beneficial effects of local dressings, the patients were divided into two groups by randomisation”.
Comment: method of generating the random sequence not reported. Author provided information that the sequence was generated by the "chit method", but it is not clear what this method is.
Allocation concealment (selection bias)Unclear risk Comment: not stated, but author provided information that allocation concealment was by means of sequentially numbered envelopes, although it is not clear whether they were sealed or opaque.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
High risk Quote: “The assessor was not aware of the treatment given (single blind)”.
Comment: blinding of participants was not done.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
High risk Quote: “The assessor was not aware of the treatment given (single blind)”.
Comment: blinding of providers was not done.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Low risk Quote: “The assessor was not aware of the treatment given (single blind)”.
Comment: blinding of outcome assessors was done and it was unlikely that the blinding could have been broken.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Low risk Comment: 3 deaths reported: 1 in the honey-treated group and 2 in the EUSOL-treated group. The causes of death were not mentioned, but the drop-out rate was < 10%, which was acceptable.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Unclear risk Comment: the information available was not sufficient to judge whether an ITT analysis had been conducted.
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasUnclear risk Comment: the baseline characteristics were not reported, so there was insufficient information available to judge whether any important form of bias existed.

Weheida 1991

  1. a

    Abbreviations

    > = greater/more than
    ≥ = greater than or equal to
    < = less than
    ≤ = less than or equal to
    ABI = ankle-brachial index
    EUSOL = Edinburgh solution of lime
    h = hour(s)
    ITT = intention-to-treat analysis
    RCT = randomised controlled trial
    TBSA = total body surface area
    SSD = silver sulfadiazine
    vs = versus

MethodsSingle-centred, 2-armed, parallel group RCT.
Participants

40 participants with grade I or II pressure ulcers.
Setting: hospital.

Country: Egypt.
Inclusion criteria: orthopaedic patients aged ≥ 21 years, ulcer ≥ 2 cm in diameter, ulcer uninfected, haemoglobin ≥ 10 g/dL, oral temperature ≤ 37.5 oC, restricted to bed or wheelchair for at least 2 weeks
Exclusion criteria: debilitant co-morbidities e.g. diabetes, cancer.

Interventions

Group 1 (n = 20): honey dressing changed daily.

Group 2 (n = 20): saline-soaked gauze changed daily.
Treatment duration: 10 days.
Follow-up duration: three months.

Outcomes

Mean time to healing:
Group 1: 8.20 days (SD 1.44);

Group 2: 9.93 days (SD 0.27).

NotesGrade I ulcer defined as moist irregular partial-thickness ulcer confined to epidermis and dermis. Grade II ulcer defined as full-thickness ulcer descending into subcutaneous tissue.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk Quote: “Subjects of the study were randomly recruited to one of the two treatment groups”.
Comment: method of generation of randomisation schedule not reported.
Allocation concealment (selection bias)Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of participants? All outcomes
Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of healthcare providers?All outcomes
Unclear risk Comment: not stated.
Blinding (performance bias and detection bias)
Blinding of outcome assessors? All outcomes
Unclear risk Comment: not stated.
Incomplete outcome data (attrition bias)
Drop-out rate described and acceptable -All outcomes
Unclear risk Comment: the study did not state whether there were any drop-outs or whether all randomised participants were followed-up.
Incomplete outcome data (attrition bias)
ITT analysis -All outcomes
Unclear risk Comment: the study did not state whether all randomised participants were followed-up and included in the final analysis, hence, we cannot judge whether an ITT analysis was conducted.
Selective reporting (reporting bias)Low risk Comment: the study protocol was not available, but the important outcome measures stated in the methods section were reported in the results.
Other biasHigh risk Quote: “Eighty percent of group I had ulcers grade I before treatment ... For group II, all the subjects had ulcers grade I, and all of which were completely healed after treatment [sic]”.
Comment: there was a baseline imbalance in ulcer grades between 2 groups; all grade II ulcers were in the saline dressing group, while all ulcers in the honey dressing group were grade I ulcers. Therefore, the ulcers in the saline dressing group were more severe.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Abdelatif 2008Not a randomised or controlled clinical trial.
Ahmed 2003Not a randomised or controlled clinical trial.
Al Waili 2003Participants did not have wounds; trial of honey mixture for atopic dermatitis or psoriasis.
Al Waili 2004aAnimal-model study.
Al Waili 2004bAnimal-model study.
Al Waili 2004cNot a randomised or controlled clinical trial.
Al Waili 2005Not a randomised or controlled clinical trial.
Albietz 2006Participants did not have wounds.
Bangroo 2005Insufficient information on healing - no response to attempts to contact corresponding author.
Berchtold 1992Did not use honey.
Biswal 2003Participants did not have wounds; trial of honey for radiation-induced mucositis.
Bose 1982Not a randomised or controlled clinical trial.
Calderon Espina 1989Could not be obtained for assessment.
Chokotho 2005No information on healing. No response to attempts to contact investigator.
Dunford 2004Not a randomised or controlled clinical trial.
Freeman 2010Not a randomised or controlled clinical trial.
Gad 1988No information on healing. No response to attempts to contact investigator.
Gethin 2005Not a randomised or quasi-randomised controlled trial.
Jeffery 2008No information on healing.
Johnson 2005Participants did not have wounds; trial of honey to prevent catheter-associated infections in haemodialysis patients.
Lund-Nielsen 2011No information on healing.
Lusby 2002Not a randomised or quasi-randomised controlled trial.
Malik 2010Unit of analysis issue - wounds randomised, not patients.
Marshall 2002Not a randomised or quasi-randomised controlled trial.
Misirligou 2003Not a randomised or controlled clinical trial.
Molan 2002Not a randomised or controlled clinical trial.
Molan 2006Not a randomised or controlled clinical trial.
Muller 1985Did not use honey.
Mwipatayi 2004Not a randomised or controlled clinical trial.
Nagane 2004Not a randomised or controlled clinical trial.
Okeniyi 2005Unit of analysis issue - wounds randomised, not participants. 32 participants had 43 wounds and individual participants may have been treated by both honey and the comparator (EUSOL). Healing rate provided by wound, not by participant.
Oluwatosin 2000Unit of analysis issue. No information on healing.
Quadri 1998Participants did not have wounds; trial of honey to prevent catheter-associated infections in haemodialysis patients. Duplicate study.
Quadri 1999Participants did not have wounds; trial of honey to prevent catheter-associated infections in haemodialysis patients.
Rivero Varona 1999Could not be obtained.
Robson 2002Not a randomised or controlled clinical trial.
Rogers 2010Insufficient information on healing.
Rucigaj 2006Insufficient information on healing - corresponding author unwilling to provide information until study published.
Schumacher 2004Not a randomised or controlled clinical trial.
Subrahmanyam 1993Not a randomised or controlled clinical trial.
Subrahmanyam 2001bAnimal-model study.
Subrahmanyam 2003No data on healing - biochemical data only.
Thurnheer 1983Not a randomised or controlled clinical trial.
Tostes 1994Not a randomised or controlled clinical trial.
Visscher 1996Not a randomised or controlled clinical trial.
Yapucu Gunes 2007Unit of analysis issue - outcomes reported by pressure injury, not by participant.

Characteristics of studies awaiting assessment [ordered by study ID]

Maghsoudi 2011

MethodsSingle-centred, 2-armed, parallel group RCT
Participants100 participants with partial-thickness burns recruited March 2010-March 2011.
Setting: hospital.
Country: Iran.
Inclusion criteria: TBSA burnt < 40%.
Exclusion criteria: not reported.
InterventionsGroup 1 (n = 50): 16-30 ml unprocessed, undiluted honey dressings changed on alternate days.
Group 2 (n = 50): mafenide acetate-impregnated gauze changed daily.
Treatment duration: until healed.
OutcomesMean time to healing and standard deviation not available.
NotesAttempting to contact authors.

Ancillary