Pain Management in Epidermolysis Bullosa

Pain is an unfortunate constant in the lives of most patients with epidermolysis bullosa (EB), especially for those with the more severe types of EB. Patients with EB have a broad spectrum of need for pain treatment, varying with the type of EB, the severity within that type, and the particular physical, emotional, and psychological milieu of each individual. Prevention of situations that precipitate trauma to the skin or exacerbate other pain-inducing complications of this multifaceted disorder is the primary goal of the treating physician. The approach to pain management is different in daily life, during intermittent exacerbations or injuries, or when hospitalizations or operative procedures occur.

Pain is an unfortunate constant in the lives of most patients with epidermolysis bullosa (EB), especially for those with the more severe types of EB. In a survey of 140 patients with all types of EB, the daily level of pain was scored at greater than 5 out of 10 in 14% to 19% of the patients with all types of EB, but present at this level in nearly 50% of those with severe recessive dystrophic epidermolysis bullosa (RDEB). Only 5% of RDEB patients were pain-free. Measurements of pain vary from study to study and methodology can influence the evaluation of degree and quality of pain, although a recent quality of life questionnaire has provided some guidelines for this evaluation. In addition, individuals vary considerably in their pain thresholds and families have different expectations as to what level of pain is tolerable. Prevention and treatment of pain is a major challenge for the clinician caring for patients with EB. The approach to pain management is different in daily life, during intermittent exacerbations or injuries, or when hospitalizations or operative procedures occur. Pediatric pain management in particular has had recent advances and requires a specialized knowledge base, which is becoming more accessible to non–pain care practitioners. An outline of pain management strategies in EB is presented in Table 1 . This review will focus on the current approaches to the management of pain in patients with EB and especially considers the importance of the delicate balance between comfort and function.

Table 1

Outline of pain management

	Daily Activities	Dressings and Baths	Acute Injury	Perioperative
Topical Rx	Occlusive dressings Protective dressings Skin grafts	Occlusive dressings Bath additives (salt, oatmeal) Adhesive removers	Occlusive dressings Skin grafts Topical lidocaine Topical morphine	OR preparation Padding Lubrication
Traditional systemic Rx	Acetominophen Ibuprofen Low-strength opioids	Acetominophen Ibuprofen Combinations Low-strength opioids High-strength opioids	Acetominophen Ibuprofen Combinations Low-strength opioids High-strength opioids	Acetominophen Ibuprofen Combinations Low-strength opioids High-strength opioids Antianxiety Rx Ketamine Nerve blocks Propofol
Nontraditional systemic Rx	Tricyclic antidepressants Anticonvulsants Tetrahydrocannabinol Dronabinol	Tricyclic antidepressants Anticonvulsants Tetrahydrocannabinol Dronabinol	Tricyclic antidepressants Anticonvulsants Tetrahydrocannabinol Dronabinol
Psychological techniques	Relaxation Visualization Yoga, meditation	Relaxation Visualization Self hypnosis	Relaxation Visualization Self hypnosis	Relaxation Visualization Self hypnosis

Abbreviations: OR, operating room; Rx, prescription.

Pain management in the home setting

Prevention of Pain

Prevention of pain is far superior to treatment. Most pain in EB is focused on the skin. Pain may exist at rest, during activities, during dressing changes or bathing, or as a result of injury to the skin. Using appropriately protective dressings, wraps and padding, and tailoring activities to the capabilities and safety of the individual can prevent unnecessary trauma to the skin. Promoting physical exercise, using physical therapy, and encouraging active enjoyable physical activities appropriate to the ability of the patient will maximize strength and flexibility, and prevent painful joint contractures and unnecessary injury. Discouraging reliance on devices such as motorized wheelchairs when patients are capable of more independent activity will maximize strength and agility. However, it is always important to weigh the benefits of lifestyle and enjoyment against the risks of skin trauma.

Sources of Pain

Most EB-related pain arises from 4 major sources: skin, bone/joints, gastrointestinal (GI) tract, and during procedures. Skin pain in EB results from blisters, erosions, and secondary cutaneous infection. Deformities of the joints from scarring and contractures compromise proper joint function and can be painful. Osteoporosis is common, and bone pain is well documented in moderate to severe osteoporosis, sometimes with vertebral compression fractures, and can respond well to treatment with bisphosphonates. GI pain starts in the mouth because oral care is difficult, and there is a tendency toward abscesses, gum disease, blisters, erosions, and dental caries. The whole GI tract is often involved, and the complications that contribute to pain from the GI tract include esophageal strictures, gastroesophageal reflux, poorly fitting gastrostomy tubes, constipation, and anal fissures. The procedures that are a painful constant include baths, esophageal dilatations, wound debridement, reconstructive hand surgery, and cancer resection. Noncutaneous pain also can result from a variety of other complications, such as pain on urination that follows urethral blistering, and eye pain often caused by corneal abrasions. These issues and their treatment strategies are discussed in detail elsewhere in this issue (see the article by Almaani and Mellerio elsewhere in this issue for further exploration of this topic.).

Topical Treatment of Pain

Open wounds tend to be most painful when exposed to air or water. Additives to the bathwater such as isotonic salt or oatmeal have anecdotally been said to reduce the pain of entering a bathtub. Occlusive, but not too adherent, dressings can provide pain relief by keeping the wound surface protected from air drying. Semiocclusive dressings, such as ointment-impregnated gauzes, gels, and silicone-based products left in place for 1 to 3 days (depending on the cleanliness of the wounds) can minimize pain. Dressings that stick to the skin are a source of pain and great anxiety in patients with EB. Adhesive removers, especially those with a silicone base, or water/saline soaks, when used before removing adherent dressings, can minimize painful and frightening dressing changes. In some patients, there has been success with the use of biologic semisynthetic grafts that seem to act as “bridges” for more rapid reepithelialization. Judicious use of topical lidocaine preparations, or soothing coating products such as sucralfate, may prevent or relieve mouth pain. In some situations, such as perianal pain with defecation or urethral pain with urination, application of topical lidocaine in small amounts can allow for more normal bowel and bladder function. Topical morphine has been an effective adjunct to pain therapy in localized areas for EB and other skin conditions, although data regarding its effect are limited. Amniotic membranes can provide instantaneous relief from pain to large surface areas such as in the neonate.

Traditional Systemic Treatment of Pain

The type of oral therapy used for pain in EB depends on the severity, chronicity, and location of the discomfort, and also depends on the individual needs, which vary widely. For example, only occasional pain medicine may be needed for daily activities, but bandage changes or baths may require pretreatment with analgesics. When injuries or infections occur, stronger medications are often needed. The role of anticipatory anxiety before dressing changes, baths, or medical procedures cannot be underestimated in this population who experience such frequent pain in their lives that their anxiety can significantly increase the need for analgesia. Conversely, strategies to reduce anxiety (discussed later) can significantly reduce the amount of analgesic used. Pharmacologic approaches to pain and anxiety include traditional and nontraditional agents ( Table 2 ).

Table 2

Pharmacologic pain therapies

Class	Generic Names	Routes	Main Uses
Opioids	Morphine Oxycodone Hydromorphone Codeine Fentanyl Others	Oral, IV, intranasal, rectal, subcutaneous, sublingual, percutaneous, others	Pain
Nonsteroidal anti-inflammatory agents	Ibuprofen Ketorolac Celecoxib Naproxen	Oral, rectal, IV	Pain
Tricyclic antidepressants	Amitriptyline Doxepin	Oral	Pain, itch
Anticonvulsants	Gabapentin Pregabalin Valproic acid Oxcarbazepine	Oral	Pain, itch Pain, itch Pain, headache Pain
Anxiolytics	Diazepam Lorazepam Midazolam	Oral, rectal, IV	Muscle spasm, anxiety
Others	Acetominophen Tramadol Ketamine Dronabinol Clonidine Sucralfate Lidocaine Bisphosphonates Salt, oatmeal	Oral Oral Oral, IV Oral, transpulmonary Oral, IV Oral Topical Oral, IV Topical	Pain Pain Pain, anesthesia Pain, nausea, itch Sleep, anxiety Pain Pain Bone pain (osteopenia) Bath-related pain

For mild pain, acetaminophen (paracetamol) and nonsteroidal anti-inflammatory agents such as ibuprofen often are sufficient. Recognition of potential hepatotoxicity with both of these agents, especially when used chronically or in high doses, needs to be shared with families. As pain increases, these medications should be continued, although other medications are added so as to avoid losing whatever analgesic effect the previous medications were contributing.

Opioids are appropriate for managing moderate to severe pain in EB. Low-potency opioids such as hydrocodone or codeine may be given. These 2 agents are limited by their combination with acetaminophen and their unpredictable effect, respectively. Using low doses of more potent opioids is effective, and avoids these limitations. However, there are side effects and concerns about the use of opioids, especially for pruritus and constipation, which are already huge problems in EB. There is also a concern about tolerance to opioids that can lead to escalating doses. However, true addiction is a rare occurrence, and no more than routine caution is warranted.

For severe pain, opioids, such as oxycodone, hydromorphone, and morphine are appropriate. Methadone is sometimes useful, but more difficult to use than other opioids, so its use is best managed by those expert in pain treatment. For procedures, transbuccal fentanyl oralets may be helpful. Overall, oral treatment is preferred, but in the very sick or terminal patient, especially in the face of metastatic squamous cell carcinoma, an end-of-life palliative approach is the compassionate one in a home-hospice type of setting. In these children intravenous (IV) infusions, and the use of patient-controlled analgesia pumps wherein the patient can press a button and receive a predetermined dose of analgesic on demand, can improve quality of life. Given that IV access is often difficult to garner and maintain in patients with EB, it is useful to know that subcutaneous opioids have been found to be useful for quite some time when the enteral route is not available. High-concentration morphine and oxycodone (20 mg/ml) are effective as well, and are reasonably absorbed via the sublingual route. In patients with EB, ankyloglossia may limit this route, and so a physical examination should be done before prescribing this route of administration. Intranasal fentanyl can also be used in end-of-life situations, at least for intermittent dosing.

Nontraditional Systemic Treatment of Pain

A variety of medications designed or approved for indications other than pain have proven to be useful in pain management. Anxiety, especially as patients anticipate dressing changes, baths, or medical procedures, can greatly add to the amount of anesthesia needed for a given situation. Anxiolytics such as diazepam, lorazepam, and midazolam may be helpful 15 to 60 minutes before a given dreaded activity. Tricyclic antidepressants such as amitriptyline have been useful for chronic pain of several types, although there has been one death from cardiomyopathy supposedly associated with its use in EB. Likewise, some anticonvulsants such as gabapentin, pregabalin, oxcarbazepine, and valproic acid are effective analgesics for several painful conditions, and may have a role in EB.

Tetrahydrocannabinol and other cannabinoids, in pill or inhaled form, have been successfully used for pain as well as nausea, anorexia, and pruritis, but tetrahydrocannabinol is illegal even for medical use in some communities and side effects can be limiting. Ketamine has been used when severe chronic pain is difficult to control, and may have a role in the care of patients with EB, especially around baths and dressing changes. The first dose or two of this medication should be administered under medical supervision.

Psychological Approach to Pain Management

The limitations of pharmacologic approaches to pain are well known. The power of psychological approaches is underappreciated, but the use of specific psychological techniques can help patients cope with acute and chronic pain, and are applicable to the population with EB ( Table 3 ). Given that the age, intellectual capacity, disease severity, and family function vary considerably among patients and their families, the wide range of available cognitive-behavioral techniques provides multiple opportunities for intervention. For example, biofeedback is a noninvasive technique by which the patient can learn body self-awareness and relaxation. It has been shown to be useful in several painful conditions and is easily learned. However, the authors find that children younger than 6 years and those with difficulty with attention span, or those with a history of posttraumatic stress disorder (ie, who cannot tolerate the intrusive thoughts that come with deep relaxation) are not optimal candidates for this modality. Coping skills and activity pacing, as well as strategizing approaches to school and other activities, can be excellent uses of a psychologist’s skills. There is a large role for parent training, as strategies can be learned by the parents that reduce the focus on pain, and allow for greater functioning of the child with chronic pain. Furthermore, adolescents with chronic pain, who showed little use of coping skills and whose parents used protective approaches, reported more symptoms. This finding suggests a role for coping skills training for the parent and the child. Procedure-centered interventions are useful and include hypnosis, guided imagery, relaxation, and virtual reality. All these techniques have been used successfully for a variety of procedures in the pediatric age group.

Table 3

Nonpharmacologic pain therapies

Skill	Situation	Patient	Parent ^a	Age Group ^b
Biofeedback	Acute and chronic pain	Yes	No	Older than 6 years
Relaxation, deep breathing	Acute and chronic pain	Yes	Yes	Older than 6 years
Meditation	Chronic pain	Yes	No	Adolescence
Coping skills	Acute and chronic pain	Yes	Yes	All, to varying degree
Yoga, Tai Chi	Chronic pain	Yes	As desired	Older than 6 years
Parent pain assistance skills	Acute and chronic pain	No	Yes	All
Hypnosis, guided imagery	Acute and chronic pain	Yes	No	Older than 6 years