Pain care for patients with epidermolysis bullosa: best care practice guidelines

Assessment of the suitability of psychological therapies for EB patients experiencing chronic and acute pain should always take into account developmental issues including age, cognitive level and psychopathology [37]. Include parents in behavioral pain management interventions [38] for children and adolescents.

Postoperative pain can be managed as for other patients in the same setting, with modifications to account for the ability to self-administer medications, prior drug exposure, and the condition of the skin at potential regional anesthesia injection/catheter sites.

The classic presentation of EB is the development of skin wounds that are painful in their own right, but which often become infected, heal poorly and frequently lead to scarring. This combination makes skin and wound pain a prominent complaint of patients with EB.

Dressings that are non-adhesive upon removal, such as silicone-based products, are helpful in reducing skin-trauma pain. Different subtypes of EB and different individuals seem to have varying dressing requirements [57]. Nutrition is important in promoting wound healing, and anecdotally, patients with poor nutritional status have more wounds and slower healing, which lead to increased pain. Experience suggests that attention to good nutrition, surveillance for superficial infection and aggressive treatment of infection reduce pain. As discussed in the section on psychological interventions, CBT is helpful for a number of painful conditions and should be applied in EB.

The pharmacological treatment of skin and wound pain is non-specific, with no evidence in the EB population to promote one treatment over another. NSAIDs, acetaminophen, tramadol and opioids are used with success. Cannabinoids have some anecdotal support. Itch is a major problem (see below) that can lead to increased scratching and subsequent development of painful wounds. Hence, managing pruritus is important to prevent wound-related pain.

Many patients with severe types of EB use long-acting opioid preparations to provide a basal comfort level. Of note, there are no clear guidelines that long-acting opioids are preferable to use of intermittent opioids for non-cancer pain [58], although there is modest evidence for opioid use, in general, for non-cancer pain in adults [58],[59]. Individualization of therapy is recommended.

Regular and frequent dosing of opioids is common and merits special attention. Regardless of the opioid chosen, chronic use of opioids may have endocrinologic effects, such as hypogonadism [60]. Monitoring should be considered, especially given the propensity for osteopenia and delayed puberty in adolescents and young adults with EB. In the absence of data, the use of opioids is recommended as clinically indicated (see Box 3).

Methadone merits particular consideration. Dose titration can be unpredictable due to long and variable half-life as well as to saturable plasma protein binding [61]. The long and variable half-life, as well as the risk of methadone-induced prolonged QT syndrome [62],[63], mandates care in its use alone and with other drugs that may also prolong the QT interval. Guidelines on electrocardiographic screening are limited [64] (especially for adult patients of smaller stature and children). Given the risk of prolonged QT and methadone’s complex and variable pharmacokinetics, it is recommended that methadone only be prescribed by practitioners with experience evaluating and monitoring its use [65]. Methadone use is, therefore, best done with input from a pain management and/or palliative care specialist.

Among the common side effects of opioids, constipation [66] and pruritus are particularly significant. Both are significant baseline problems in EB and the reader is referred to the sections on gastrointestinal pain and pruritus.

The pain of extensive wounds has a quality suggestive of neuropathic pain; both are often described as `burning’ in quality. There is evidence supporting the use of gabapentin for neuropathic pain in other conditions [67]. Medications such as tricyclic antidepressants and gabapentin have shown anecdotal success in EB skin pain in a child [68], as well as for adult patients with acute skin pain due to burns [69]. The potential for tricyclic antidepressants to prolong the QT interval means that caution should be taken using this class of medications in RDEB patients, who are at risk for developing cardiomyopathy [70], as a lethal outcome in this setting has been reported [71].

For localized wounds, topical lidocaine jelly (2% concentration) has been used anecdotally. Morphine mixed in hydrogel formulations has been used in different types of localized painful wounds [72],[73] but has only limited anecdotal experience in EB wounds [74] (see Box 3). Use of these medication vehicles raises questions of absorption and systemic effects that require further investigation before full recommendations can be made. Limited anecdotal evidence supports the use of keratinocyte hydrogel dressings for poorly healing wounds and RDEB [75].

Blood draws and intravenous access as well as the need for skin biopsies are minor technical procedures that can be very distressing, especially for children. Topical anesthetics are commonly used in non-EB populations with good effect. Amethocaine appears to be more effective than a eutectic mixture of local anesthetics (EMLA®) [76]. These may have a role when applied to intact skin, but cannot be recommended for use on wounds due to unknown rate and extent of absorption of lidocaine. Blistering as a localized allergic reaction to EMLA® (or its contents) has been rarely observed, indicating caution in its use even on intact skin. Lidocaine injected with a small gauge needle is a standard approach to superficial analgesia in all age groups. Additionally, it is recommended that bicarbonate be added to buffer the pH of the lidocaine to reduce the pain of injection [77]. As noted above, CBT (for example, distraction and relaxation) is effective in the acute pain setting [21] and should be employed whenever possible in conjunction with medication management (see Box 1).

Prevention and rapid healing of wounds through non-adherent dressings, optimal nutrition and infection control are priorities.

Bathing and bandage changes are a source of significant recurrent pain and anxiety for patients with EB.

Oatmeal and salt have been added to bath water to reduce the pain of immersion [78]. The former may have anti-pruritic, cleansing and protective properties for dermatologic conditions in general [79] that may be similarly effective in EB. Salt is added to make the water isotonic, which has anecdotal support from many families of patients with EB including preliminary survey data from EB families [80]. Isotonic saline (0.9% NaCl) is 9 grams of salt/1 liter of water; total amount of salt varying according to the desired water volume. Bleach and vinegar are anecdotally helpful in drying the skin and reducing bacterial colonization, which some patients find comforting while others report increased pain at the wound sites. The salt water does not require plain water rinse, whereas vinegar and bleach baths require rinsing to reduce the risk of itch. Many patients elect to reduce the frequency of bathing as a simple measure to minimize bath-related pain. Anecdotally, starting the bath by immersing the patient still in his/her bandages can ease the transition into the water and help reduce the pain of removing the dressings. Other patients find drafts from heating and cooling systems to be painful on open wounds, so attention to general environmental factors is recommended (see Box 4).

Analgesics used by patients with EB have included enteral opioids, NSAIDs and acetaminophen. The nasal route may permit administration of medications when intravenous access is absent [81]. Fentanyl works well by this route for non-EB patients in the perioperative setting [45], for breakthrough cancer pain (see section on Breakthrough pain medication at the end of life) and has been used for acute pain management in the emergency department with success [46]. Butorphanol is a mixed agonist-antagonist that can be used via the intranasal route and is effective both for pain (for example, dental postoperative pain [47]) as well as for opioid-induced pruritus. Fixed dose spray is available for outpatient use in the United States, which limits the ability to adjust for patient size. Timing of medication administration should be adjusted to match expected peak analgesia with anticipated peak pain (see Box 4).

Ketamine can be administered enterally for wound care pain, for which there are data from adult and pediatric burn populations [82],[83] but not for EB patients. The IV form of ketamine given orally has been used with variable success for other chronic pain conditions [84] as well as in cancer patients [85] and in pediatric palliative care [86].

Inhaled nitrous oxide has been suggested for pediatric wound care in EB in some texts and review articles [44],[87], but its use in EB patients has not been studied or reported. Nitrous oxide has been used for painful procedures in other settings [88] and is available in both fixed 50:50 and variable combinations with oxygen. Depending on the delivery system (mouth piece, face mask, or nasal mask) concerns arise about environmental pollution and exposure of health care personnel [89]. In the absence of evidence of efficacy, concern must be raised about repeated use for wound care or dressing changes because of longstanding evidence of megaloblastic bone marrow changes and neurologic abnormalities due to inhibition of methionine synthase and cobalamin activity with repeated exposure to nitrous oxide [90],[91].

The pain caused by baths and dressing changes is commonly cited by families as generating anxiety in the patient, which in turn is stressful for the caregiver. Medications used for acute anxiolysis in this population include midazolam, diazepam and lorazepam and are considered good treatment for acute anxiety in other populations (for example, children for dental procedures, [92],[93]; prior to adult burn procedures [94]). In addition to anxiolysis, the pre-procedural use of benzodiazepines offers the possibility of anterograde amnesia which may prevent the development of increased anxiety with repeated procedures. When using benzodiazepines in combination with opioids, care must be taken to avoid over sedation (see Box 4). As response to each medication will have individual variation, dose adjustments should be made carefully and preferably one drug at a time, when more than one is being administered.

In addition to medication management, recommendations from caregivers include preparing all materials ahead of bandage removal to reduce the amount of time wounds are exposed to air. Involving children in the process at as early an age as possible helps them to develop a sense of control. Maintaining room temperature at a moderately warm level has also been recommended. CBT can be applied to treating the anxiety and pain associated with bathing and bandage changes (see section on psychological approaches, above).

Bathing and dressing changes are recurrent sources of both pain and anxiety. Therapy should focus on both symptoms, using environmental, psychological and pharmacologic approaches.

Gastrointestinal complications are common in children and adults with EB with specific complications linked to different subtypes [95]-[97].

Oral ulceration, blistering and mucositis are the most frequent gastrointestinal complications in patients with EB [98]. While oral ulceration can occur in all types of EB, it is most common and problematic in patients with the severe types of this disease. Oral ulceration can be extremely painful and lead to difficulties in feeding and maintaining dental hygiene. Apart from oral analgesics, topical preparations are available. Sucralfate suspension has been used to prevent and manage oral blisters in five children, 6- to 11-years-old, with RDEB when applied four times a day for six months [99]. The number of blisters reduced within three weeks and pain reduced within one week (see Box 5).

Polyvinylpyrrolidone-sodium hyaluronate gel (Gelclair®) either used as a mouth rinse or applied directly to a mouth lesion in children, has been used anecdotally in EB. Secondary evidence comes from two recent reviews which showed that Gelclair® may be useful as an adjunctive therapy in decreasing the painful lesions of oral mucositis in cancer patients [100],[101]. Chlorhexidine gluconate and benzydamine hydrochloride mouth spray is used regularly in EB patients at the London centers with reported benefit but has not been evaluated systematically. Secondary evidence for the potential efficacy of this intervention exists for treating the pain of acute viral pharyngitis in adults [102].

Patients with EB are at high risk for gastroesophageal reflux disease (GERD) - especially infants with generalized EBS, JEB and patients with severe generalized RDEB who can develop esophagitis [95]. While children with GERD may not complain of dyspeptic symptoms until they are older, crying and sleep disturbance are commonly associated with this symptom. Management is guided by standard treatment in non-EB patients, and may involve treating the reflux with antacids, histamine H₂-blockers and proton pump inhibitors and, rarely, surgery [103],[104] (see Box 5).

Esophageal stricture formation and dysphagia are most common in patients with severe generalized RDEB with a cumulative risk of developing strictures or stenosis rising steadily from 6.73% at age 1 year to 94.72% at age 45 years [105]. However, strictures can also be seen in other subtypes of EB including Kindler syndrome [106]. Dysphagia and delayed progression of food through the stricture can present with retrosternal chest pain. Esophageal strictures, if symptomatic, require treatment with a fluoroscopically guided balloon dilatation with peri- and post-operative steroids administered to reduce the recurrent stenosis rate [107]-[109] (see Box 5). Acute symptoms can respond temporarily to oral dexamethasone or nebulized budesonide, based on anecdotal evidence. A recent case report examined the use of daily oral viscous budesonide therapy (0.5 mg/2 mL budesonide nebulizer solution mixed with 5 g of sucralose and maltodextrin) in two children with RDEB who had recurrent proximal esophageal strictures [110]. Both children had a reduction in the rate of stricture formation and symptoms of dysphagia.

Constipation has been shown to be present in 35% of children with all types of EB [95] and can cause abdominal pain and pain on defecation as well as lead to perianal trauma. A case of colonic perforation and early death resulting from severe constipation in DEB has been described [111]. Chronic perianal pain during defecation can produce stool withholding behavior which exacerbates constipation. Chronic opioid use may contribute to poor bowel motility. First line management is prevention with dietary manipulation; however, patients with severe types of EB often require the regular use of a laxative (see Box 5). Polyethylene glycol is effective clinically in treating constipation in children and adults with EB, with empiric evidence of efficacy in adult [112] and pediatric [113] non-EB cohorts.

A subgroup of children with RDEB may develop colitis, presenting with abdominal pain and other symptoms [95],[114]. Dietary restriction and anti-inflammatory drugs, such as sulfasalazine, have been used but with variable effects on controlling the colitis [95].

Perianal blistering and ulceration is common and debilitating in children and adults with severe types of EB. Topically, sucralfate has been shown to be superior to petroleum jelly in facilitating anal fistulotomy healing and lessening wound pain [115]. Sucralfate suspension has also been used to lessen the pain of oral and genital ulceration in patients with Behcet's disease [116]. Anecdotally, topical sucralfate combined with Cavilon™ (an alcohol-free liquid barrier film that dries quickly to form a breathable, transparent coating on the skin, containing hexamethyldisiloxane, isooctane, acrylate terpolymer, polyphenylmethylsiloxane) appears to improve pain in perianal lesions of some patients with EB. Non-surgical treatment is of small benefit for both pain and healing of chronic anal fissures [117], with recommendations of topical diltiazem and glyceryl trinitrate followed by surgery if needed in adults [118]. No data on anal fissure treatment in EB patients exist (see Box 5).

EB affects the gastrointestinal tract in its entirety. Pain that originates from ulcerative lesions may respond to topical therapy. GERD and esophageal strictures have nutritional as well as comfort implications and should be addressed promptly when found. Maintaining good bowel habits and reducing iatrogenic causes of constipation are crucial.

Musculoskeletal complications are common and frequently painful for patients with EB. These conditions include pseudosyndactyly, osteopenia, back pain, fractures and occasional co-morbid rheumatologic disorders.

Pseudosyndactyly affects hands, feet, ankles and wrists. Painful hyperkeratotic lesions develop on the soles of patients with EBS. Occupational therapy approaches can improve function and decrease pain via use of adaptive equipment and specially designed orthotics and clothing. Physical and occupational therapy play crucial roles in encouraging patient mobility. For weight-bearing patients, careful attention to footwear, nails, orthotics and hyperkeratosis management are important aspects of pain care [119]. Referring patients to programs to maintain or regain strength, to prevent or minimize joint contractures, and to optimize mobility is recommended based on anecdotal evidence (see Box 6). Coping skills training and activity pacing can enhance effectiveness of therapy [120].Surgical intervention has had some success in increasing mobility and reducing pain [121]. EB patients can also have inflammatory arthritis [122],[123]; appropriate imaging can be helpful in determining inflammatory causes of pain. Given that inflammatory markers are usually elevated in EB patients, these markers alone are not likely to be useful to diagnose joint pathology.

Osteopenia, osteoporosis and fractures are now well recognized and commonly seen in patients with the severest types of EB [124]-[126], as a cause of bone and joint pain. The causes are multifactorial and include reduced mobility, delayed puberty, limited exposure of the skin to sunlight, inadequate nutritional intake for metabolic requirements and chronic inflammation. Chronic inflammation causes increased osteoclast activity [127],[128].

As a consequence of the osteoporosis, a significant proportion of patients develop fractures. The incidence of vertebral fractures in patients with RDEB is unknown, but may be underestimated due to the fact that fractures of the lumbar and thoracic spine may be clinically silent, or present without overt or localized back pain on palpation [125]. Anecdotally, however, some patients can present with back pain, in which case a high index of suspicion should be maintained. Treatment of osteoporosis and derivative pain is based upon standard treatment of osteoporosis in non-EB patients, which relies on vitamin D and calcium supplementation, exercise and bisphosphonate treatment [129] (see Box 6).

Anecdotally, bisphosphonates have been found useful in treating patients with evidence of osteoporosis without fracture. Bisphosphonates appear to improve fractures on annual X-rays and lead to a noticeable improvement in pain. Indirect support for the use of bisphosphonates comes from its use in rheumatologic and other pediatric conditions, associated with osteopenia [130],[131] and resolution of back pain [131],[132], but efficacy specifically in patients with EB has not been formally studied.

Older patients with EB can have back pain. Beyond osteopenia-related issues, biomechanical causes can be involved. Foot blisters and painful hyperkeratosis can cause abnormal gait and compensatory postures. Further, impaired mobility can add a myofascial component to pain. Management of back pain includes optimal foot care, assessment of primary and secondary mechanical factors, evaluation and treatment of osteopenia and fractures, physical therapy, standard analgesics and CBT interventions. Back pain treatment in the EB population is extrapolated from basic principles recommended for the general population [133], for lack of EB-specific evidence (see Box 6).

NSAIDs are routinely used for bone and joint pain of a variety of types and are appropriate for these types of pain in EB. Care should be taken to monitor for side effects, and the cyclooxygenase-2 inhibitors may be useful in those patients who experience improved pain control but note increasing blood loss from wounds, or who have gastrointestinal upset with standard NSAIDs. Acetaminophen does not affect bleeding and can be useful. Tramadol and opioids are also useful for more severe pain. Some prefer use of long-acting opioid preparations, with methadone being the only one available in liquid form. Limitations in methadone use are discussed in sub-section on systemic approaches under Skin and Wound Pain.

Bone health should be optimized with calcium and vitamin D supplements as needed, maintenance of maximum mobility, minimization of joint deformity and monitoring for/treatment of pubertal delay. Routine screening for bone mineral density may be useful to ascertain cases of osteopenia before they progress to osteoporosis and fractures. Care must be taken not to overlook inflammatory joint disease, as pain secondary to this will respond to disease modifying therapy. Multidisciplinary treatment modalities are helpful in addressing back pain and apply to such pain in the EB population as well.

In the severe forms of EB, pain starts immediately, and great care needs to be taken in most of the activities of daily living. Infants with EB require careful attention to environmental factors at a higher level than for older children but otherwise can receive pain care using guidelines for specific types of discomfort.

Pain assessment should be completed on all neonates with EB at regular intervals and as needed (see Box 8). A valid neonatal pain scale should be used, considering both physiologic and behavioral measures. Some examples include: the Premature Infant Pain Profile (PIPP) [139],[140], the Neonatal Pain Agitation and Sedation Scale (N-PASS) [141], the Crying, Requires oxygen, Increased vital signs, Expression and Sleepless pain scale (CRIES) [142], and the Neonatal Infant Pain Scale (NIPS) [143]. The Face Legs Arms Cry Consolability (FLACC) scale is recommended for infants between 1 to 12 months [144]. These pain scales have been validated for use by nurses, although training could be generalized to non-nurse care givers and family members. Pain should be reassessed frequently during and after interventions and until comfort is achieved based on a combination of one of the above scales and clinical judgment. Analgesic interventions should match degree or level of pain. Of note, infants, especially neonates, seem to be a higher risk for respiratory compromise [145],[146] due to reduced clearance of opioids in infants younger than two months [147],[148]. Therefore, careful clinical and cardiopulmonary monitoring is crucial when providing opioids to this population (see Box 8).

As for older patients, procedures are one of the major sources of pain for infants with EB. Wound care specifically requires a multidisciplinary team approach to ensure consistent and optimized pain control. There is evidence that a variety of pharmacologic and non-pharmacologic interventions are helpful in both term and pre-term infants [149]. Therefore, pain management interventions should precede all scheduled painful procedures, such as dressing changes, bathing and venipuncture. The range of analgesics and the routes by which they can be administered are the same as for older patients. Oral sucrose is an analgesic unique to young infants and can be used alone for mild pain (for example, immunization pain [150]) or in conjunction with other analgesics as well as physical and environmental interventions for more severe acute pain [40],[151].

To maintain appropriate moisture levels and facilitate the healing of wounds, dressings should be non-adherent as for older patients and appropriate in size. Infected wounds will require more frequent dressing changes [57],[152]. Changing dressings one limb at a time is advocated in infants, to reduce the likelihood of having the skin rubbed off the opposite limb by feet kicking together, causing new, painful lesions (see Box 8). This approach also decreases the chance of bacterial spread from a colonized wound to an uncontaminated area [57],[78]. For baths, adding salt to the water is recommended as for older patients (see subsection on environmental treatment under Bathing and Dressing Changes).

In addition to environmental adjustments, many infants will require analgesics with bath and dressing changes. NSAIDs, acetaminophen and opioids are all used, as for older patients (see Section-Bathing and Dressing Changes) (see Box 8). Codeine is not recommended, when alternatives are available, as neonates lack the capacity to metabolize the drug into active metabolites, and clinical responses are highly variable at all ages, due to polymorphisms in codeine’s metabolic pathway [153],[154].

Severely affected newborns with deep tissue damage may require extensive pharmacologic support to achieve a level of comfort (see Box 8). These infants may require around the clock or continuous infusion of opioids and an adjuvant. A transition to methadone for better steady state levels should be considered (refer to sub-section on systemic approaches under Skin and Wound Pain) for caveats about methadone use). A case study has shown effective pain control in an infant with severe chronic pain (and possibly pruritus) when treated with gabapentin [155]. Patients receiving frequent opioid treatment may require extra care in avoiding opioid-induced constipation and in maintaining adequate caloric intake.

Oral ketamine has been used to supplement opioids when pain associated with dressing changes is severe [156]. Use of ketamine raises concerns due to findings of adverse neurodevelopmental effects in young animals who received prolonged intravenous infusions of ketamine [157]. However, these effects are not known to occur in human infants and are unlikely to occur with small doses administered at intervals.

Infants benefit from the same range of analgesics as older patients. They can uniquely benefit from oral sucrose for brief painful episodes. Careful monitoring is crucial in infants receiving sedating medications. Babies with EB and their parents benefit from close physical contact like any other families. Holding and cuddling can be done safely, with scrupulous attention to lifting and handling in order to prevent new lesions and pain.

The epidemiology of death in EB varies by type [158], but is not limited to dermatologic causes. Patients with JEB, generalized severe type are at greatest risk of fatality early in life from a range of causes [159],[160]. Persons with RDEB may succumb in early to mid-adulthood from multiple causes [161]-[163] whereas patients with generalized types of EB simplex are at risk of laryngotracheal complications [164].

The palliative approach to pain experienced by individuals who are facing life-threatening illness addresses the physical, emotional and spiritual suffering of the patient and includes support for the whole family [165]-[167] (see Box 9). Squamous cell carcinoma is frequently diagnosed in patients with severe subtypes [168] and can present challenges typical of cancer-related pain when it metastasizes. The World Health Organization ladder approach to pain care for those patients with cancer and other persistent illnesses recommends a two-step `ladder’ as a framework for pain care [169].

Opioids have a role in EB pain management, as previously indicated in these guidelines (see Box 9). Patients in the palliative phase of their illness may be given an oral opioid sustained release medication [170]. Opioids should be titrated against pain and side effects, with differences in approach needed depending on issues such as opioid tolerance and rate of development of new pain problems [170]. However, if appropriate opioid increases are not effective, it is important to consider pharmacologic tolerance, poor absorption and neuropathic pain. Tolerance can be addressed by rotating the opioid to capitalize upon incomplete cross-tolerance [171],[172]. In the face of poor absorption, parenteral therapy may be needed (see below). If neuropathic pain is suspected, methadone may be an option to consider. It has N-methyl-D-aspartate (NMDA) antagonist action in addition to mu-agonist properties common to standard opioids, and can be beneficial for neuropathic pain [173] and does not rely on renal excretion [61], which may be reduced in the palliative phase of EB [87]. Although a recent meta-analysis could not establish differences in efficacy among types of opioids for neuropathic pain, it was determined that intermediate term (weeks to months) use of opioids for neuropathic pain may be helpful [174]. Cautions in the use of methadone are discussed in the sub-section on systemic approaches under Skin and Wound Pain.

Many EB patients will have been treated with adjunctive agents such as amitriptyline or gabapentin earlier in their illness, often with good effect [87],[155]. These both may take a period of time to achieve full analgesic effect and usually need to be given by the enteral route. Ketamine is more rapidly effective and can be given orally [84]-[86],[175] or used subcutaneously (see below). It should be noted that when ketamine by-passes hepatic first pass metabolism, the relative proportion of norketamine is reduced and the patient may experience more sedation and hallucinations and less analgesia for a given dose [175]. Other options for addressing neuropathic pain (see Box 9) in terminal care include opioid rotation to methadone (see above), which can also be included in a subcutaneous infusion (see below).

Parenteral administration of analgesia may be needed in the palliative phase, when ability to take enteral medications is no longer an option or if rapid escalation of therapy is needed. There has been an historic reluctance to use continuous subcutaneous infusions, due to the fear of precipitating further blistering. However, subcutaneous infusions have been reported to be tolerated in the final days of life in an adult EB patient [176] (see Box 9).

In non-EB patients with cancer pain, the subcutaneous route of morphine is effective to a similar degree as the intravenous [177]. Other alternatives, such as adherent transdermal delivery systems, need regular removal and replacement. Repeated subcutaneous/intramuscular injections are very frightening for children, as are attempts to obtain IV access. Alternatively, sites of subcutaneous needle insertion last reasonably well [87],[177]. If subcutaneous sites do become inflamed, some benefit has been shown from adding low dose dexamethasone to the infusion [178], although this has not been used to our knowledge in children with EB.

Even when good baseline pain relief has been achieved, most patients will require occasional `breakthrough’ doses of analgesia. Uniformly effective breakthrough dosing protocols have not been determined for children with EB at end of life, although there are general recommendations from several international sources [169],[179] and data to support the use of up to 20% of total daily opioid consumption [180],[181] in adults with cancer. In general, a short-acting, immediate release form of opioid should be given at approximately 10% to 15% of the total background opioid dose of the previous 24 hours. If rescue dosing is used frequently and consistently, then the baseline opioid dosing needs to be increased. Individual patient factors should be taken into consideration (including prior opioid exposure, renal and hepatic function, other medication use) and consultation with an expert in pain management and/or palliative care is recommended. The same principle is recommended for opioids given via all routes of administration. When very rapid onset is needed, transmucosal administration of opioids may be preferable (see Box 9). Commercially available transmucosal preparations of fentanyl are available in doses likely to be suitable for older children and adults. Evidence supports the use of transbuccal fentanyl for breakthrough pain in cancer patients [182]. An additional benefit of fentanyl is that it is not dependent on renal excretion. In some centers, the injectable formulations of morphine or diamorphine have been used buccally at around a third of the standard enteral dose (equivalent to the intravenous dose), allowing more flexibility of dosing. It is also important to remember that extreme anxiety may confound pain perception or expression and that there may be benefit in offering additional doses of buccal midazolam where this is felt to be a significant factor. Therapy should be targeted at specific symptoms whenever possible, although combination therapy is not unusual. Breakthrough analgesia should be offered in the face of unexplained `agitation’ in case of undiagnosed pain, after which medication for primary agitation/anxiety may be considered. While it is likely that both of these would cause a degree of sedation at higher doses, this should not be the primary aim of treatment.

Palliative pain care is an expected part of care for EB, which in many cases is life-limiting in nature. All basic principles of palliative care apply as they do for other terminal disease states.

Itch is a prominent, debilitating and damaging symptom for children with EB, but the mechanisms which lead to the manifestation of pruritus are poorly understood [183]. Promising new insights into the causes and potential treatments of chronic itch in animal models [184], in human chronic itch generally [185] and in recovering burn patients [186] may hold potential for application in the EB population.

Multiple environmental and behavioral approaches to address itch have been suggested [183],[187] and include: prevention of dry skin (systemic hydration and emollients), gentle debridement of dry/dead/crusted skin, prevention and treatment of skin wound infection; maintaining/supporting the healing process by attention to anemia and nutritional status, limiting damage to the skin by avoiding shear forces imposed by scratching (short nails, occlusive barriers, patting rather than pulling or tearing at a site), avoiding overheating and using measures to keep the body cool (see Box 10). CBT is useful to reduce habitual scratching behaviors (see section on psychological approaches). It is important to avoid and treat secondary causes when present (such as drugs, environmental itch triggers, underlying co-morbidities). Opioid-induced itch in EB can be a problem and a difficult side effect to balance against the desired analgesia; opioid rotation may be helpful.

Pharmacological therapies include traditional oral antihistaminic medications (see Box 10). Some patients prefer sedating formulations at bedtime (for example, diphenhydramine, hydroxyzine, chlorpheniramine) and others non-sedating preparations during the day (for example, cetirizine, loratadine and fexofenadine). Efficacy is variable and recommendations are based on anecdotal experience for lack of good evidence in EB and other dermatologic conditions. Centrally acting medications, such as gabapentin and pregabalin, have evidence for efficacy from the burn literature [186],[188],[189] and may have application in EB. Many of these medications have also been used successfully for neuropathic pain (see sub-section on adjunctive measures for neuropathic pain under End of Life Pain). Antidepressants with nortriptyline re-uptake inhibitory actions have been used for various pruritic conditions with some evidence for efficacy, with mirtazapine showing promise [190]-[193]. Low-dose cyclosporine has been used in a single case of dominant dystrophic EB to reduce generalized itching [185],[194]. Anecdotal success has been reported with ondansetron in EB; however, the same had been reported for pruritus from cholestatic jaundice, although controlled trials did not confirm efficacy [195]. Similar suggestions were made related to the pruritus of uremia [196],[197], leading to recommendations that ondansetron should be considered, although clinical trials are needed in EB.

Other medications that have shown sporadic clinical success in treating itch in EB include: cyproheptadine; selective serotonin re-uptake inhibitors (SSRIs; fluoxetine, paroxetine, sertraline, fluvoxamine) [193]; tricyclic antidepressants (doxepin, amitriptyline, nortriptyline) [192]; opioid antagonists (naloxone, naltrexone); kappa receptor agonists (butorphanol, dextromethorphan, nalbuphine); other 5-HT3 receptor antagonists (granisetron, dolasetron); antipsychotic agents (olanzapine, pimozide) and cannabinoids. These agents and the NK-1 receptor antagonist aprepitant may prove to be useful in certain subsets of patients, although evidence to guide therapy is lacking [198] and practitioners are encouraged to pursue the aforementioned therapies based on patient response to prior medications, potential interactions within the patient's medication list and medication availability (see Box 10).

It is common practice for medications from different drug classes to be used concurrently and for agents in the same class to be rotated due to the observation that a particular medication may have improved efficacy after intermittent drug holiday.

A combination of environmental, cognitive-behavioral and pharmacologic therapies is available for use for EB-related pruritus, which can be a severe symptom of the disease.