Pain from wounds is categorized as baseline or background pain and two types of breakthrough pain: volitional incident pain and nonvolitional incident pain . Baseline pain is the pain that is present without manipulation or movement of the wound and is related to the underlying pathological processes of the wound (ischemia, inflammation, infection, maceration). Breakthrough pain is defined as ‘transitory exacerbation of pain experienced by the patient who has relatively stable and adequately controlled baseline of pain’ . This implies that ‘end of dose failure’ is not truly a breakthrough pain but just inadequate titration of the baseline pain opioid .
Breakthrough pain is divided into ‘pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger’  and has been given various names. Incident pain is the predictable sudden escalation of pain with physical movement or other activity (e.g. bowel movement with perirectal wound). Procedural pain includes dressing removal, cleansing and redressing and sharp debridement. Operative pain refers to manipulation, debridement or grafting that requires general anesthesia. This article focuses on wound-related procedural pain (volitional incident pain) related to activites such as dressing changes, cleansing and sharp debridement, but the principles and strategies can also be used in nonvolitional incident pain.
PREVALENCE OF BREAKTHROUGH PAIN IN WOUNDS
No studies specifically measuring the prevalence of breakthrough pain in patients with wounds secondary to advanced illness exist. A systematic review of any type of pain prevalence in pressure ulcers in 2008 that included several studies of over 100 patients found a prevalence of pain that ranged from 37 to 66% . Those studies using validated pain scales found higher prevalence of pain. Stage of the ulcer was the most important factor related to the prevalence of the pain with the more advanced stage leading to a higher prevalence of pain. The same systematic review did not find a relationship between pain and dressing changes suggesting that dressing change pain is probably caused by a multitude of factors and not entirely related to the wound itself.
CAUSES/MECHANISM OF BREAKTHROUGH PAIN
There are multiple factors causing pain in wounds in advanced illness. The underlying causes of the wound such as local tissue ischemia, chronic inflammation and infection all contribute to the factors affecting healing  and stage of wound, and therefore pain. Most chronic wounds are in older adults and one of the postulated reasons, besides the increased prevalence of advanced illness, is the older adult's reduced ability to respond to a physiological insult  Others have proposed that the older adult's greater prevalence of severe and disabling pain is due to an inadequate response to stress . One could postulate a relationship between uncontrolled pain and healing of the wound.
Originally, wound-related pain was thought to be somatic pain secondary to tissue damage. However, persistent inflammation and tissue damage can lead to central sensitization and neuropathic pain. A small study that did an in depth review of the pain in patients with pressure ulcers found that most often the patients reported their background pain as having the quality of burning . Another literature synthesis of the quality of wound pain reported descriptors consistent with neuropathic pain such as stabbing, shooting, pins and needles . It is important to recognize this as allodynia and hyperalgesia of the wound and surrounding tissue will occur rendering the wound and surrounding tissue painful even with exposure to air.
A systematic review of the qualitative aspects of ulcer pain noted that most commonly patients reported pain during dressing changes . This pain was usually at the site of the wound bed and surrounding skin but could radiate out from the wound. The increased intensity and radiation of the pain could persist for hours after the dressing change was completed. Most significantly, patients often felt that healthcare providers underestimated the intensity of the pain during dressing changes. Patients equated poorly managed pain with healthcare providers not believing they experienced pain [11,12]. Anticipation of procedural pain would lead patients to avoid dressing changes.
One of the major causes of breakthrough pain with dressing changes is the removal of the dressing causing damage to the healing tissue and surrounding skin . The method of removing the dressing and the skills of the healthcare provider in removing the dressing can be critical as well as the nature of the dressing itself. Other causes of pain include the temperature of products used on the wound as the hyperalgesia can render these sensations painful rather than just cool. Last, but not least, there is the anticipation and fear that can come with repeated dressing changes in which breakthrough pain is not controlled.
ASSESSMENT OF BREAKTHROUGH PAIN (INCLUDING COGNITIVELY IMPAIRED)
The assessment of breakthrough pain is part of the overall pain assessment in wounds. It is important to ask the location, quality and intensity and triggers for all the pains a person is experiencing. A brief pain inventory may be a helpful tool for those who are able to self-report. It is helpful to ask patients to rate the intensity of the pain before, during and after their dressing change to get the best understanding of procedural pain.
In general the use of validated pain tools will lead to more standardized pain assessment and the recommended scale for intensity is the Numerical Rating Scale in which pain is rated from 0 (no pain) to 10 (worst pain possible) . Characteristics of neuropathic pain are distinguishable from nonneuropathic pain in that those with neuropathic pain will describe the pain with more intense hot, cold, sensitive surface pain than the less intense deep and dull pain described in nonneuropathic pain .
PAIN ASSESSMENT IN COGNITIVE IMPAIRMENT
One of the major barriers to wound pain assessment is cognitive impairment. The more cognitively impaired, the less likely the patient is to self-report pain . As the prevalence of breakthrough pain is so high in chronic wounds, clinicians should always ask about pain or discomfort. A validated quality of life scale in adults with an Mini-Mental Status Exam (MMSE) score above 10 (Logsdon et al.)  uses the words ‘poor’, ‘fair’, ‘good’ and ‘excellent’, which suggests that simple questions with a limited choice of verbal answers may be an effective method of eliciting information. Using simple language, such as ‘Do you have pain right now?’ and ‘is the pain mild, moderate or severe?’, to obtain a verbal report is a direct and concrete way to inquire about pain without relying on memory.
Pain that occurs with dressing change may be relatively easy to observe, as it is known that changing dressings can be painful. However, other processes of care, mobilizing or movement by the patient may also cause breakthrough pain and the patient's distress response may not be easy to separate from the behavioral and psychological symptoms of dementia (BPSD). Proxy pain reports by caregivers and relatives can be unreliable , so behavioral observation may be the best method of assessing pain and monitoring response to analgesics . Behavioral observation is a process of monitoring distress behavior throughout the day, sometimes for weeks, watching for associated events or activities that may result in or exacerbate the distress behavior. It is reasonable to presume that the same distress behavior seen with a dressing change may be seen with breakthrough pain, but the distress behavior may also be due to the need-driven behaviors (e.g. need to urinate etc) and resistance-to-care behaviors (e.g. fear or anxiety), which are considered part of BPSD. As there are no specific behaviors known to reliably indicate pain, it is important that all distress behaviors are viewed as a possible sign of pain in this population.
The American Geriatric Society has developed a list of common pain-related behaviors  and many behavioral observation scales have been developed . There is no single behavior that indicates pain, rather it is the pattern of distress behavior as it relates to activity, other needs and pain interventions that ultimately will be helpful.
The rational approach to pain assessment in individuals with advanced cognitive impairment incorporates multiple sources of information including resident report of pain; professional staff, caregiver or family report of pain; distress-related behavior not responding to other interventions; and observation during dressing changes, care or mobilization.
MANAGEMENT OF BREAKTHROUGH PAIN IN WOUNDS: NONPHARMACOLOGIC
The clinician's attitude toward pain is a key part of the pain-management strategy. Assuming that the wound is painful and accepting what the patient says about the pain is essential in beginning to control the pain. This situation is particularly true in procedural pain as the patient must trust providers not to induce pain by removing the dressing, cleaning, debriding and redressing the wound. It is essential to give patients the control over the procedure by stopping when the patient tells us they are in pain or asks to stop. Repeated painful wound dressing changes beyond the control of the patient lead to anticipatory anxiety and fear and demoralizes the patient. It is also unethical and negligent to repeat a dressing change that is causing severe pain . Adequate pain relief must be sought. Systematically assessing and documenting the pain and analgesic strategies that have been tried is evidence of quality practice .
In patients nearing the end of their lives, in whom comfort is more important than healing the wound, the frequency of dressing changes must also be considered. Reducing the dressing changes to the minimal amount to keep the wound comfortable and dry may be the best practice.
Nonpharmacologic strategies for procedural pain prevention are in Table 1.
MANAGEMENT OF BREAKTHROUGH PAIN IN WOUNDS: PHARMACOLOGIC
The control of breakthrough pain in wounds depends upon adequate control of the baseline pain. The analogy is that if the valleys are filled in, the mountains are not as high. This principle was trialed in a small study in which the baseline pain medication was increased beyond the level of adequate control, resulting in reduced intensity of breakthrough pain in bone metastases pain . With slow titration of opioids above the level for adequate control of baseline pain, there was a tolerable side-effect profile.
Administering short acting opioids to control incident pain has been the standard of care for decades. Improving control through use of different routes has been reported in small studies for decades. The intravenous route was often the route of choice in early days but required acute care monitoring. The development of the first portable infusion pump was in the 1970s and was used for continuous pain control. The development of programmable infusion systems that would allow the patient to administer a breakthrough dose – Computerized Ambulatory Drug Delivery system – was developed in the 1980s and has grown more sophisticated and well tolerated since then. The subcutaneous route is preferred because it is less invasive and requires less maintenance.
The infusion pumps are accurate but expensive ways to deliver breakthrough medications, and to many patients who wish a nonmedical approach to their care they represent unwanted technological intervention. In patients with anasarca, coagulopathy or inflammatory reaction to the subcutaneous needles, or in patients with poor veins due to multiple episodes of chemotherapy another route is much preferred.
The search for noninvasive methods to deliver opioids shifted to mucosa as small molecules that are lipophilic can pass into the circulation in significant amounts. The thickness of the mucosa is a significant factor in the onset of action. The nasal mucosa is 40–80 mm and has faster onset than either the sublingual mucosa (100–200 mm) or buccal mucosa (500–800 mm) [23▪].
The sublingual route  offers many advantages to the oral route as it delivers drugs directly to the central systemic circulation and bypasses the hepatic first pass metabolism resulting in greater bioavailability of the drug and a more rapid onset of pain relief. The disadvantages of the sublingual route include the unpalatability of opioid preparations but, more importantly, the need to hold the medication under the tongue for several minutes. This limits the amount of medication that can be delivered, and those with cognitive impairment, may swallow reflexively resulting in poor absorption through the stomach mucosa. pH plays an important role in the absorption from the sublingual and buccal routes. The normal pH is approximately 6.5, but this can be altered by mouth breathing, reduced salivation, stomatitis, vomiting, nutritional status and age.
Sufentanil has become the agent frequently used by palliative care providers for incident pain, although there are only case reports to support its use [25,26]. Methadone has been successfully used in a small well designed trial as a sublingual opioid for breakthrough cancer pain .
The intranasal route offers even more advantages. The mucosa offers a direct connection with the systemic circulation, but there is evidence that there is direct access to the Central Nervous System (CNS) because some of the drainage of the nasal cavity is into the cavernous sinus . The nasal route can accommodate higher volumes than sublingual, and the prerequisite of having the patient hold the medication in the mouth is avoided . This is particularly useful in patients with cognitive impairment. Disposable intranasal devices have been trialed with sufentanil and found effective for breakthrough cancer pain .
With the progression of understanding about breakthrough pain in cancer, there has been change in the thinking around its management [31▪]. A recent review reveals that most breakthrough pain onsets and reaches maximum intensity in 15 min, lasts only 60 min [32▪] and is consistent with previous literature . The ideal opioid for the management of breakthrough pain would, therefore, be an opioid with rapid onset and of a shorter duration than most of the typical short-acting opioids. Fentanyl with its high lipophilicity can be absorbed through multiple routes, penetrates the CNS rapidly, has a rapid onset and short duration and has no significant active metabolites . The first commercially available fentanyl for breakthrough pain was the oral transmucosal fentanyl citrate lozenge, but in the last few years there have been a variety of new oral dissolvable, buccal and intranasal preparations.
The formulations that have arrived in the last 5 years have added value from just taking fentanyl injectable and holding it under the tongue or spraying it intranasally. The formulations available usually have a pH adjustment for the sublingual or buccal mucosa to aid in absorption and the intranasal formations have vehicles like pectin to help it adhere to the nasal mucosa. A recent in-depth review of the formulations [34▪▪] notes that trials compare the formulations with placebo, and in this respect, all demonstrate equivalent efficacy and safety. The characteristics as reported from product labeling are based on trials on healthy individuals and in general the nasal sprays have a more rapid onset than buccal tablets or films and, in turn, these are better than the oral transmucosal lozenge [35▪]. The selection of the actual product will depend on patient-dependent factors such as site of disease, preference, ease of administration and financial coverage of the medication.
There has been concern that the fentanyl breakthrough formations may be subject to more risk for abuse because of the rapid onset of the drug. This comes in part from the realization that although these medications are indicated for breakthrough cancer pain, they are frequently used off label . A review of the trials of breakthrough fentanyl products in patients found a 1–3% incidence of aberrant drug-related behaviors in the trials [37▪], consistent with other studies of abuse-related events in chronic opioid therapy. Consistent assessment, screening for abuse risk and monitoring of patients are recommended .
OTHER ADJUVANT AGENTS
Ketamine, an NMDA receptor agonist, used in subanesthetic doses, has found a place as a useful neuropathic pain adjuvant in palliative pain management  and in acute postoperative pain management . In doses closer to anesthetic levels, it has been used in combination with sedatives such as midazolam or propofol for painful procedures in emergency settings and proven to be effective and well tolerated . It provides both sedation and analgesia in high-enough doses but does not have any adverse effect on respiratory drive or airway reflexes. The main concerns with this drug are hallucinations and recovery agitation in adults. In patients with procedural pain not responding to the usual opioids, it is reasonable to try adding subanesthetic doses of Ketamine (0.5 mg/kg per dose once daily) as an adjuvant medication to opioids. It can be taken orally, 1 h prior to dressing change, or given subcutaneously.
Midazolam, widely used as a sedative in addition to opioids for procedural sedation , can be useful for procedural pain from dressing changes. It is effective for anxiety during procedures or in the cognitively impaired, who may not understand the need to remain still during the procedure.
The principles of any pain management strategy include regular and frequent re-evaluation of the pain in order to maintain analgesia. This is particularly essential in patients with cognitive impairment. Pain-management strategies in patients with severe cognitive impairment advocate trialing analgesics while continuing to monitor the frequency and intensity of distress behaviors. The dosing or strength of the analgesic is escalated if there is no positive change in the behavior. When distress behavior is reduced, the analgesic is titrated to a balance of distress and intolerable side effects (usually sedation). If the distress behavior returns, it may be increasing pain or possibly a new source of distress.
Managing breakthrough pain in patients with wounds in advanced illness contributes to their quality of life and assists in the maintenance of dignity. Structured assessment and ongoing monitoring of the pain is a key concept. Nonpharmacological strategies are equally important in managing the pain as drugs. Control of the baseline pain is essential to control the breakthrough pain. Newer formulations of fentanyl offer an onset of action and duration that more accurately match that of the breakthrough pain.
Conflicts of interest
This article was written without funding.
This article has not been published before or been offered as a manuscript elsewhere.
I have received honoraria from Purdue Pharma for educational events. I do not receive any funding from any of the products described in this article.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 123).
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