Innovative pain management solutions in animals may provide improved wound pain reduction during debridement in humans: An opinion informed by veterinary literature

Abstract

Painful animal husbandry procedures are routinely performed in a range of livestock species without analgesia. Recently, innovative strategies have been developed to address wound pain in these animals. In particular, a farmer‐applied “spray and stay” approach that is administered directly to open wounds was developed (Tri‐Solfen® Medical Ethics Pty Ltd., Melbourne, Victoria, Australia). This strategy anaesthetises the wounds immediately upon their formation, with long‐lasting effect. This development, described as a “pain management revolution,” has become firmly established in the Australian livestock industries and has global potential. The positive outcomes of this approach provide insights and highlight potential benefits that may be accrued from its use in human wound care, providing rapid‐onset wound analgesia and/or anaesthetising wounds prior to cleansing and debridement procedures. If these benefits are realised from a clinician and patient perspective for wound debridement as an initial indication, it could provide new horizons in pain management for a spectrum of wound‐related procedures. Evidence from use in animal husbandry does support the concept that multimodal anaesthesia holds great potential in the field of wound management across many procedures.

Abbreviations

EMLA

eutectic mixture of local anaesthetics

NHS

National Health Service

NSAID

non‐steroidal anti‐inflammatory drugs

1. INTRODUCTION

The presence of dead or necrotic tissue (including slough) on the surface of any wound will delay wound healing. Debridement that facilitates the removal of such barriers to healing is an integral part of wound bed preparation and comprises the T (tissue removal) element in the TIME continuum to promote healing endorsed by most key opinion leaders and consensus groups.1, 2 Wounds heal faster when debrided often by trained health care professionals. Published studies have shown that faster and more complete healing was achieved with more frequent debridement regardless of wound type, size, or duration.3, 4 Weekly or even more frequent debridement resulted in shorter healing times compared with less frequent debridement. Education and training for proper debridement practices should not be limited to physicians but should include general staff members in order to make the flow of wound care more efficient. Nearly twice as many venous and diabetic foot ulcers were shown to have healed completely with frequent debridement compared with those treated less frequently (50% vs 28%).4 The clinical professional has a range of options to achieve debridement, and choice will depend on the pain threshold of the patient, type of necrotic tissue, and where the patient is being treated.

The fastest debridement procedure is sharp debridement usually associated with the use of a scalpel or similar instrument. The more “patient friendly” approaches, such as the use of hydrogels, may take weeks, with many visits to facilitate dressing changes for costly and time‐consuming re‐application of the hydrogel.5 Other innovative approaches include the use of newer pad technologies to clean the wound surface. For example, monofilament fibre technology is available that lifts up the slough and debris, binding it between the fibres to facilitate removal.6 Hydrosurgical debridement has also been successfully used in burn wound debridement and cases of challenging wounds.7

Patients with wounds often experience pain. However, there is evidence that this is often underestimated or mismanaged by health professionals.8 In addition, there are many psychological and emotional factors associated with living with a wound that can affect patients' perception of pain, such as anxiety, stress, fear, and depression.9

Pain associated with both acute and chronic wounds can be an unpleasant experience and can present in two main forms. The first is nociceptive pain that arises from damaged tissue and is often described as aching or throbbing. The second type is neuropathic pain resulting from damage to or dysfunction of the nervous system. It differs in character from nociceptive pain, and patients describe it as having sensations of burning, tingling, or shooting in nature.10 It has been suggested that dressing removal, wound cleansing, debridement, and inappropriate dressing selection can contribute to wound‐related pain.11

As a specific example, it has been reported that over 70% of patients experience pain associated with their chronic leg wounds, ranging from moderate to severe.

Wound pain and intensity is highly variable. It is not an accurate predicator to make clinical assumptions that specific wound types or wound size will define the type of pain the patient is experiencing. Pain intensity can be stable over time, vary day to day, and may increase.12 Ineffective wound pain management can result in delayed healing and lack of compliance by the patient.

Patients who undergo sharp debridement may feel greater pain than other approaches, and this may impact their compliance with undergoing the necessary number of debridements to achieve an optimal wound bed that can start to progress towards healing. In addition, because of the level of procedural pain, they may ask for an immediate cessation of treatment at any stage during the process. Sharp debridement of non‐viable tissue is a frequent treatment modality for leg ulcer patients and has been suggested as the gold‐standard approach.13, 14 However, the procedure is not well tolerated, and patients will often ask the clinicians to cease before the debridement is completed because of pain.15 Some patients may deny future consent for the sharp debridement if the first experience was painful. This also impacts the confidence of trained physicians in achieving the depth of tissue removal necessary for optimising the process of wound bed preparation. This poses difficulties in providing appropriate care and in achieving healing in a timely manner. Delayed healing eventually creates additional costs and deterioration in the patient's quality of life. The UK National Health Service (NHS) advocates a patient‐centred approach that promotes physical comfort, including pain management.16

Current therapeutic options for wound pain relief during debridement include use of oral analgesics for minor manipulations to the wound and dressing changes if required. Where there is a high probability of pain developing in procedures, such as sharp debridement of the wound surface, drug‐based creams (eutectic mixture of local anaesthetics [EMLA] cream, Aspen Pharma Trading Ltd) are used, which can take between 30 minutes and 1 hours to take effect prior to use of the scalpel.17, 18 This creates the practical challenges of in situ retention and possible re‐application.

Injection of local anaesthetics such as lidocaine has been an option prior to debridement. Multiple sites may be required, and the procedure may have to be carried out by a trained, experienced physician. The onset of action is quick, and the duration of action is generally up to 60 minutes. The anaesthetic may cause a burning sensation when injected, and time and care are needed to be successful.

Surgical wound infiltration with local anaesthetics has continued to increase in popularity since the mid 1990s.19 It is relatively inexpensive, technically not difficult, and may potentially reduce postoperative discomfort. Even though pain results from complex physiological mechanisms that involve multiple receptors in both the central and peripheral nervous systems, single or monotherapy with opioids has been a foundation of post‐surgical pain management.

The use of multimodal analgesia involves the administration of two or more analgesic agents that act through different mechanisms with the goal of improving post‐surgical pain management. Non‐opioid alternatives, for example, non‐steroidal anti‐inflammatory drugs (NSAIDs), acetaminophen, and local anaesthetics, are recognised as effective components of a multimodal pain regimen postoperatively.20

It is proposed that an unmet need exists to develop effective products for anaesthetising wounds rapidly and effectively prior to cleaning, debriding, or suturing. As highlighted previously, significant pain for patients undergoing these procedures can be present, creating a need for painful injections or systemic medications. It can also terminate the procedure prior to completion because of patient intolerance of the resulting pain.

2. MATERIALS AND METHODS

A semi‐systematic scoping literature search strategy of available peer‐reviewed published evidence was conducted, including free‐text terms to identify relevant studies indexed on the PubMed database. Key medical subject heading terms included wound debridement, methods of debridement, pain management during debridement, and patient concordance with debridement. In addition, literature on innovative new multimodal approaches to wound analgesia in farm animals was reviewed, including the safety and efficacy of a topical local anaesthetic and antiseptic combination formulation and impact on pain alleviation and wound healing. The authors accept that the conclusions relate to a semi‐systematic review with an opinion component, although this is based on extensive clinical published research experience. As with all emerging technologies, research and clinical findings from the majority of work on use of Tri‐Solfen (Tri‐Solfen Medical Ethics Pty Ltd., Melbourne, Victoria, Australia) have been captured continuously since the earliest publications of studies commenced in 2005.

3. RESULTS

Within the field of animal husbandry, an innovative technology has emerged that has the potential to complement the various approaches to human wound debridement.21 It comprises of a “stay and spray” approach for open wounds designed to alleviate pain, minimise bleeding, and provide antiseptic cover with a rapid onset and prolonged duration. On application, it forms a long‐lasting bio‐compatible film or barrier over the wound, creating its own intrinsic analgesic properties. The formulation acts as a slow‐release carrier for the actives, including the two local anaesthetics, lidocaine hydrochloride (5% w/w) and bupivacaine hydrochloride (0.5% w/w), in addition to the vasoconstrictor adrenaline acid tartrate (0.00451% w/w) and the antiseptic cetrimide (0.5% w/w). The formulation keeps the actives in contact with, and promotes diffusion into, the wound. The combined synergies create a prolongation of overall analgesic effect beyond the expected duration of actives (up to 24 hours) and enhanced wound healing of open wounds and/or those that are likely to remain otherwise untreated for prolonged periods.22, 23 Adrenalin works synergistically to minimise vasodilation caused by the local anaesthetics, minimise bleeding, and prevent systemic absorption and risk of toxicity.

Farmer‐applied “spray‐on” topical anaesthesia and antiseptic formulation (Tri‐Solfen) was introduced in Australia in 2005 and was registered for widespread commercial use in 2012 to manage the pain and hasten the healing of the open wounds incurred during the “mulesing operation” in sheep.21, 22 This procedure is conducted as a lifetime prevention against myiasis (flystrike) in susceptible sheep on many Australian sheep farms, mostly involving Merino lambs at high risk of the condition because of the presence of “breech wrinkle”. The conformation of folded or ‘wrinkle‘ in the breech area readily retains urine and faeces and provides an attractive environment for deposition of the eggs of the sheep blowfly Lucilia cuprina. Following hatching, the blowfly larvae burrow deeply into adjacent tissues to the penetrating wounds in afflicted animals, rapidly causing the animal to become moribund because of blowfly strike. Untreated cases usually die.

Myiasis is one of the most serious causes of morbidity and mortality in Australian sheep. Long‐term genetic breeding of “fly‐resistant” sheep is occurring. However, the mulesing procedure, involving the surgical removal of skin from each side of the breech and the tail to form a smooth scar, remains the most effective method to provide life‐time protection against myiasis. Previously, in the absence of registered pain relief options, the mulesing procedure was performed without analgesia, resulting in welfare concerns for the lambs at the time of surgery. Tri‐Solfen used during mulesing was readily and widely adopted by farmers in Australia, enabling the sale of wool classified as ‘PR‘(pain relief) and improved welfare of sheep susceptible to flystrike during the extended period required until genetic alterations of Australian Merino sheep phenotypes can progress sufficiently to successfully address the risk of myiasis. It is estimated that 6 to 7 million lambs are treated annually, with approximately 100 million animals having now received treatment with Tri‐Solfen since the product was registered.

Following the first field reports that lambs appeared far more amenable to being moved after surgery that included pain management with Tri‐Solfen, trials using a variety of methods to measure pain and wound healing, including systematic behavioural assessments, quantitative sensory testing of wounds with von Frey monofilaments or algometry, and photography of treated and untreated wounds, established that effective wound analgesia occurred for at least 24 hours, with improved wound healing.22, 23 Plasma local anaesthetic levels were well below toxic thresholds, even when large relative doses were applied (up to 50 mg/kg lidocaine in lambs). Importantly, the application of the combination topical anaesthetic formulation delivered directly onto the wound peri‐operatively or immediately postoperatively was immediately recognised to have broader applications in livestock husbandry. Following extensive research trials involving many routine aversive husbandry procedures, Tri‐Solfen has now been demonstrated to be safe and efficacious in managing pain and improving healing of acute surgical wounds incurred during surgical castration and tail docking of lambs,24 surgical castration and dehorning of calves,25, 26 and surgical castration of piglets.27 It is also proving effective in chronic wound conditions. A study in dairy cattle undergoing debridement of hoof abscess involving treatment with Tri‐Solfen reported evidence of significantly reduced pain during the procedure and reduced lameness following surgery.28 It also has potential for use for improving wound management in these and in other species, including shearing cuts in sheep; lameness caused by hoof injuries and abscesses in sheep; open wounds in horses, dogs, cats, and other companion animals and wildlife; and, potentially, for superficial lesions resulting from viral infectious of the epidermis (PW, unpublished data). Important findings from previous and current studies include confirmation of rapid onset of wound analgesia and positive welfare outcomes for an extended period well beyond that expected when the duration of action of the anaesthetic actives was considered, in addition to improved pain management when used with an NSAID for pain relief29, 30, 31 and, on occasions, improved productivity.32

The inclusion of an NSAID in the pain management research in animals has aimed to develop a “best practice” multimodal regimen approach to pain management, with practical approaches to deliver both blockage of nociception and amelioration of wound sensitisation examined. A method for oral delivery of NSAIDs (meloxicam as Ilium Buccalgesic, Troy Laboratories, Australia) was developed in Australia and has been shown to be efficacious for procedures in both lambs and calves.31, 32 Widespread adoption by farmers of the addition of an oral NSAID to the procedure currently remains uncertain. However, the use of topical anaesthetic formulation accompanied by intramuscular injections of NSAIDs, administered by beef farmers under veterinary advice, does appear to be increasing in Australia, particularly with recent research confirming both efficacy and productivity improvements with this multimodal approach for use in beef cattle husbandry procedures.32, 33, 34

The recent developments in the Australian livestock farming sector indicate that a new paradigm has emerged in addressing the welfare concerns of aversive procedures used routinely in livestock husbandry for centuries.22 This innovation is increasingly achieving international recognition.35 However, international producers and consumers of livestock products do need greater awareness of the improved attitudes and practices of animal welfare on many Australian farms through the increasing adoption of routine farm animal pain management strategies. Furthermore, the positive large‐scale safety and efficacy trials conducted regularly in animals since 2005 have identified the potential for similar new innovative topical analgesic wound management strategies for use in acute traumatic and chronic wounds in humans.

4. DISCUSSION

Pain elicits awareness of visceral or environmental insults and has a broad range of physiological and sociological dimensions. Wound pain involves the three stages of nociception, sensitisation, and central cognition. Following a noxious stimulus, peripheral nociceptors, with enhancement by the release of pain‐sensitising chemical mediators, produce peripheral to central activation of sensory neurones via the peripheral nerves and then dorsal horn of the spinal cord, stimulating sensory areas of the brain, resulting in central cognition of pain.

As pain expression varies considerably within and between species, developing objective clinical assessments that determine what an individual animal may be experiencing is challenging, particularly as the behaviour of “prey” species is to generally limit the display of pain incurred by injury. Furthermore, the widely held assumption that animals at an early age suffer less pain than those that are older has led to a general acceptance that aversive husbandry procedures should routinely be conducted at an early age. This likely derives from both the ease of restraint that can be applied in younger animals and considerations that an animal with a less developed central nervous system (CNS) may experience less pain than an older animal where the CNS is more mature. This may be of relevance in altricial species but is likely to be less relevant in precocial species, including ruminants, where the CNS is sufficiently advanced at birth to enable neonates to be ambulatory and respond to noxious stimuli in the early neonatal period.

Pain management of ruminants as performed routinely by veterinarians has generally involved the prior use of sedatives to provide restraint, often with compounds that have some analgesic properties (eg, xylazine, ketamine), in addition to the prior injection of a local anaesthetic into the surgical site or vicinity of a local peripheral nerve to achieve blockage of nociception. More recently, NSAIDs have been recruited to ameliorate sensitisation. This multimodal approach aims to capture the effectiveness of individual agents in optimal dosages, offering theoretical synergies in acute pain prevention, potentially minimising the side effects from each drug.36 However, in many farming situations, provision of pain relief by veterinarians is impractical, yet farmer adoption of multimodal approaches is difficult because of restrictions on the availability of drugs for widespread use. However, the development of Tri‐Solfen has enabled the positive welfare effects of inhibiting wound nociception by spray‐on topical anaesthetic formulation by farmers. Importantly, Tri‐Solfen has been shown to be safe, practical, effective, and is popular with farmers. Inclusion of a farmer‐applied NSAID to ameliorate wound sensitisation is considered a logical additional strategy and is being encouraged. Furthermore, this multimodal approach avoids the administration by farmers of centrally acting drugs such as opiates to modify cognition; this is considered very challenging and even undesirable as it would require greater veterinary supervision than is practical and potentially creates food safety concerns.

In terms of wound pain in humans, most of the literature is focused on general pain and how it impacts patient well‐being or the detrimental effects of the presence of pain during dressing changes. This has led to a plethora of dressing developments aimed at decreasing pain by minimal adherence to the wound bed. The importance of debridement and its potential to convert a chronic wound into a more acute state is well recognised, although few publications exist highlighting the specific need to develop approaches to dampen pain during debridement. Anaesthetic creams containing single pain‐relieving compounds have a place, and their use is evidence‐based, although they have some drawbacks, as listed previously. It is proposed that a topical fast‐acting, long‐lasting, easily applied approach using anaesthetic combinations combined with adrenaline to allow targeted action and limited systemic absorption may be safely and effectively applied in humans as the evidence from numerous studies in animals suggests this approach could potentially transform the practice of debridement. From a clinician confidence and patient acceptability point of view, rapid optimisation of the wound bed by removal of unwanted material would potentially facilitate faster closure. Innovation in translating what is known about Tri‐Solfen in animals to the human wound model is well underway. Work is ongoing to develop user‐friendly application approaches, and clinical trials are planned treating venous ulcers to demonstrate the anticipated benefits and create the beginnings of a strong evidence base. Other indications of potential use could include use in surgical incisions prior to closure, laceration management in the emergency department, open abdominal surgery, and use in ambulances and military/mass casualty situations.

Farmer‐applied spray‐on Tri‐Solfen, particularly used in a multimodal approach with NSAIDs, is a new paradigm for addressing the welfare concerns of aversive procedures used routinely in livestock husbandry. This approach is becoming firmly established in the Australian livestock industries and potentially has global implications. It is suggested that not only do international consumers of animal products need to be made aware of the improved welfare attitudes and practices on many Australian farms, but these advances may be of benefit to the welfare of numerous global livestock populations for a range of painful practices. This “pain management revolution” empowers farmers to reduce the suffering experienced by their animals undergoing aversive husbandry procedures, with markedly enhanced animal welfare. Importantly, it addresses concerns raised in activist‐led campaigns promoting improved welfare of farmed animals and is an important market risk management intervention that could be routinely adopted in the global livestock industries. This work could also provide insights into the use of this approach in human wound care that could transform existing practices in interventional pain‐relieving approaches, benefiting clinical practitioners and, more importantly, their patients.

Roberts CD, Windsor PA. Innovative pain management solutions in animals may provide improved wound pain reduction during debridement in humans: An opinion informed by veterinary literature. Int Wound J. 2019;16:968–973. 10.1111/iwj.13129