Preventing and Modulating Learned Wound Pain

Wounds cause pain but the consequences of wound pain remain largely unknown. Studies from other disciplines have shown that pain can contribute to the long-term physiological and emotional consequences of the pain experience, setting the stage for the phenomenon referred to as “learned pain.”

Providing ways to help patients avoid learning pain — ie, modulating pain anticipation/expectation, peripheral nerve blocks, pretreatment analgesics, biophysical technologies, modification of patient and provider behavior, judicious choice of dressings, and behavioral therapies — has been found to play a significant role in decreased physical and emotional discomfort and improved outcomes. Existing evidence on pain suggests that wound pain most likely consists of a combination of local, systemic, and learned phenomena retained by the patient as long-term “pain memories” as well as acute reaction to stimuli. Until the consequences of wound pain are fully appreciated, healthcare providers should consider application of research findings from other disciplines to reduce pain and prevent the learning and development of pain memories.

      Wounds cause pain and caring for a wound contributes to the long-term physiological and emotional consequences of having pain. The International Association for the Study of Pain (ISAP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”¹ Pain also has been described as a response to an unpleasant stimulation of individual nociceptors in the periphery when perturbated at a given area of the body and transmitted to higher centers in the brain.² The World Union of Wound Healing Societies (WUWHS)3 defines wound-related pain as “a noxious symptom or unpleasant experience directly related to an open skin ulcer.” The ISAP definition comes closest to considering the impact of pain on the whole person by including both the physiological and psychological components of emotional experience.

     Robust findings reported in the literature substantiate the significant impact of brain neural networks on the pain experience and include: 1) the nervous system is able to reorganize and learn responses and behaviors that are retained as “pain memories”^4,5; 2) pain expectations are learned from past experience and affect pain perception6,7; 3) pain expectations profoundly influence pain-related brain activation, need for analgesic medication, wound care treatment adherence, and healing outcomes^8-10; and 4) clinician and patient actions during therapy affect brain activity and wound healing, providing an opportunity to influence patient outcomes. This article presents an overview of a compendium of information on pain found in the literature — human studies comprising randomized controlled trials, case studies, and qualitative studies, as well as basic science studies on animals — to enhance understanding, and ultimately practice, regarding the pain experience as it relates to wound care.

Brain Function Related to Pain

     Useful technologies. Brain functional activity can be observed using neuroimaging technology such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), high-resolution electroencelphalography (EEG), magnetoencephalography (MEG), and transcranial magnetic stimulation (TMS). Using PET and fMRI facilitates measure of regional blood flow and metabolic activity linked with function-related changes in neuronal firing levels.⁷ This information has allowed scientists to image the path of stimulation in the brain and visualize storms of electrical pulses sweeping through its specific regions and to create brain or cortical maps, much like topographical maps, to show the pathways for transmission of specific types of information within the brain. Brain maps have been used 1) to delineate the major structures of the brain pain matrix (thalamus, hypothalamus, insula, anterior cingulate cortex, primary somatosensory cortex, and prefrontal cortex) and 2) to show electrical storms are activated by stimulation of receptive fields in the skin comprising neuron populations encoded and translated into thoughts, emotions, sensations, and memories and stored in the cortex.^7,11,12

     Imaging provides the ability to objectively assess pain and outcomes of pain treatment but it is costly, not readily available, and lacks information about the mechanisms involved. Based on the evidence already derived from research, assumptions can be made about how pain affects brain centers. Imaging research is progressing rapidly and continuously providing new information about pain associated with different disease states. Chronic wound pain has yet to be studied in this manner.¹² Evidence has been selected that appears to be applicable to the wound patient population, at least until information more specific to wound care is available.

     Pain without stimulus. Pain may be generated without external stimulation — eg, in individuals with peripheral neuropathy.¹³ The ISAP acknowledges that pain is a subjective experience that may arise without any peripheral nociceptive input.¹ Of 41 healthy adults participating in a qualitative study⁵ who used mental concentration and visualization of pain, 66% reported symptoms including numbness, pins and needles, moderate aching, or definite pain, demonstrating the possibility that prolonged activation may have induced the learning of long-term symptoms.

     Neuroplasticity = learning. Neuroplasticity is defined as, “the ability of the brain to change (reorganize) in response to external stimuli, experience, or damage.”¹⁴ The term describes the pliancy and malleability of neuronal connections, the basis of learning and repair.⁷ Brain reorganization (neuroplasticity/learning) is demonstrated in studies^4,15-17 of patients with chronic low back pain, stump and phantom limb pain, chronic regional pain syndrome (CRPS), and focal hand dystonia. A randomized, comparative study⁴ with fMRI of 10 patients with upper extremity amputation and phantom limb pain showed that cortical representation of the mouth area had invaded the region formerly represented by the amputated extremity and that the shift was correlated exactly with the magnitude of phantom limb pain. In a case series¹⁷ of 13 patients with phantom limb pain, positive correlations (P = 0.001) were found between the amount of cortical reorganization and the magnitude and repetition of painful stimulation as measured on the standard pain intensity scale. In a comparative clinical study¹⁸ of patients with focal hand dystonia (a disabling movement disorder of the hands in persons who perform rapid finger movements — eg, pianists and court reporters) using MEG technology, a difference was demonstrated in the location of the hand representation of the somatosensory area of the cortex between 17 healthy subjects and 17 patients with the disorder. The patients with hand dystonia demonstrated somatosensory degradation (reorganization) that correlated with the motor dysfunction and may represent aberrant learning. Most studies of pain processing in the brain have been conducted on healthy, normal patients as opposed to those with chronic pain. Yet Tracy’s¹² systematic review found evidence of altered cortical processing in all patients with chronic pain; in one study, 26 patients with chronic low back pain (as seen on fMRI) had a 5% to 11% loss of bilateral neocortical gray matter volume (brain atrophy) related to pain duration compared to a matched number of controls. The potential ramifications of chronic pain on the entire nervous system, such as the pain experienced by wound patients, needs to be appreciated and avoided as much as possible.

     Brain maps. Brain maps show the brain relies on large populations of neurons acting in concert using an encoding process to form a memory.¹⁹ Brain maps of the cortex can be modified by sensory inputs, experience, and learning, sprouting and forming new synaptic connections over time.⁷ The somatosensory and somatomotor cortices — located adjacent to each other in the cortex and known to be in close communication (see Figure 1)²⁰ — represent the body surface in a orderly fashion along the postcentral gyrus, roughly following the order of the spinal dermatomes.²¹ The spinal cord is segmental; nerves from each spinal segment (dermatome) and nerve branches overlap and innervate the segments above and below (ie, lumbar 1 affects lumbar 2 and thoracic 12). This may help explain why patients in an international survey²² reported pain not just in the wound but also in “the surrounding skin and elsewhere.”

     As represented by the homunculus, the face, hands, and genitalia — which are endowed with the most sensory receptors and large receptive fields — have greater representation than the trunk and extremities (see Figure 1).²⁰ When pain repeatedly occurs in one body area, such as the recurrent leg pain associated with chronic venous disease or an amputation (stump and phantom limb pain), the area on the sensory homunculus representing the painful area increases in size, much the way muscles do when exercised repeatedly.^4,17 This change in the homunculus causes somatosensory degradation or “smudges” the representation of the pain characteristics. Hence, pain may be experienced not only in the ulcer area, but also in the entire receptive field of the specific as well as neighboring dermatomes. The patient loses the ability to discriminate, localize, and/or describe the nature of the pain,⁴ which may encompass a significantly larger area than the wound or be at a distance from the wound site throughout the dermatome associated with the area. This is a form of maladaptive plasticity — ie, where changes that generate spontaneous and exaggerated pain with no protective or reparative function occur.^7,23 The pain becomes a secondary pathology. Painful stimulation such as that associated with wound care has the potential to stimulate maladaptive plasticity.

     Phantom limb. Almost all patients who have amputations experience phantom limb pain.^4,24 Following amputation, altered afferent inputs and synaptic changes associated with resprouted nerve endings occur in both the stump and affected cortical areas that have lost connections. In complete or partial limb amputation, an end bulb forms at the terminal of the nerve. This leads to development of a neuroma, formed when the nerve axons cannot or only partially reconnect. These neuromas send abnormal, ectopic nerve signals — ie, signals that do not come from the nerve endings. These signals are sent through the central nervous system (CNS) to the somatosensory cortex,²³ which may partially explain why patients with phantom limb pain experience maladaptive cortical reorganization.¹⁷ Usually, patients requiring amputation as a result of chronic vascular disease are elderly and often have extended periods of pre-amputation pain.²³ Following amputation, post amputation nociceptive pain further alters pain signals. For some but not all individuals, this establishes the conditions for phantom limb pain.

     In wound care, individuals become sensitized to repetitive sharp or mechanical debridement and dressing changes, associating these activities with pain to become pain memories. This increased sensitization is not only expressed by the patient, but also would be visible and measurable during brain imaging studies such as those conducted on patients with phantom limb pain. Memory traces are present subconsciously and appear without warning even at the mere mention of a painful experience like bandage removal. This associative learning explains how the expectation of a sensation elicits a reaction.

     Sharp wound debridement excises dead tissue and severs the connection of nerve endings of healthy tissue in the adjacent skin, disrupting peripheral neuronal connections and the afferent nerve transmission system.²⁵ In debrided chronic wounds, the connections are cut off for extended periods of time. In this author’s interpretation, this allows local and cerebral nerve endings to resprout and accounts for ectopic activity transmitted to the CNS and a component mechanism for persistent pain reported by patients with leg ulcers, much the same as phantom limb phenomena after amputation.

Neuronal Pathways

   Information travels multidirectionally between the periphery and the CNS. For example, a pain signal may be received from the receptive field of the skin or from the primary somatosensory cortex or another part of the brain pain matrix and transmitted primarily from the thalamus and hypothalamus via three main pathways: the spinothalamic, spinoreticularthalamic, and spinohypothalamic tracts of the spinal cord. The thalamus and the dorsal and ventral horns of the spinal cord act as relay stations, transmitting signals as required.^2,12

     According to IASP,¹ the pain threshold is “the least experience of pain a subject can recognize.” Repetitive painful stimulation delivered in short or long intervals lowers neuronal thresholds and promotes widespread nervous system sensitization and abnormal processing of nociceptor input, resulting in pain, hyperalgesia (exaggerated pain response), or allodynia (pain experienced from normally non-noxious stimuli).^1,13,25 When the peripheral and central nervous systems become dysfunctional, the result is neuropathic (stinging, burning, throbbing) pain as a secondary complication of the wound. (Describing the complex cellular pathology involved is beyond the scope of this article.) The nervous system can learn a new associative behavior that triggers pain memories and an emotional response at the mere anticipation of pain.^8,26

     The painful stimuli transmitted via the CNS pathways to the cortex, picked up by neuronal networks of the pain matrix, and retained as pain memories is the same mechanism humans use to learn and retain all memories.⁶ For example, most people remember the pain of pulling off an adhesive bandage. The brain learns to recognize and pair this sensory experience with this stimulus. Pavlov is well known for his experiments inducing salivation in dogs when he rang a bell at each feeding. After a period of time, just ringing the bell elicited the expectation of food and triggered a salivation response — associative learning had occurred and was stored in the dog’s CNS as a memory.

     Ekman and Friesen²⁷ examined facial muscle combinations and created a taxonomy of 43 facial expressions called the Facial Action Coding System (FACS) for reading and interpreting the human emotional state. The FACS was developed by studying facial expressions based on the activation of combinations of specific facial muscles. The result is the FACS that is used in the psychological field to analyze emotional states. Levinson et al²⁸ collaborated to measure and document changes in autonomic nervous system (ANS) activity with changes in facial expressions. They used normal adult volunteers and measured changes in heart rate and body temperature, which are physiologically associated with emotions of fear, anger, and sadness. Half the group was asked to remember and relive a stressful experience. The other half was told to create corresponding facial expressions for each of the emotions on their faces. The results were that the same ANS physiological responses occurred in both groups. It seems that both groups used associative learning in the development of emotional memories. Access to these memories apparently used different mechanisms. For group two, the facial muscles, that as shown on the homunculus man figure have huge representation in the somatosensory and somatomotor cortices, received signals from the muscles that were sent to these brain areas, subsequently accessing the associated learning centers. Perhaps associative learning can help explain why the faces pain scales, which use common facial expressions for the emotions associated with pain, show validity, reliability, and reproducibility for measuring pain in the elderly and children.^29,30 Clinicians who become familiar with common facial expressions that evoke emotions for sadness, anger, pain, and fear will be better able to “read the story” in the patient’s face. For example, a patient is preparing for a usually painful dressing change and the facial muscles produce a tight-lipped expression. The nervous system is preprogrammed by anticipation of the procedure, so the tight lips may become a trigger for the associated learned pain without local stimulation. The signal is interpreted not just as pain, but also as emotions. Similar to bandage removal, when a patient experiences wound-related pain (eg, dressing change, debridement, movement, or repositioning), a pain memory is created or reinforced in the pain matrix area of the brain and may partially explain the variety of pain severity experienced. Responses are individual.

Pain Expectation and Cognitive Modulation

     Another example of associative learning is pain expectation. High pain expectation can become the wound patient’s reality. Conversely, low expectation has the ability to reduce perceived pain. Using fMRI, Koyama et al⁸ studied 10 healthy adult volunteers. Pain was induced experimentally at different intensities with intervals between testing. During the intervals, subjects came to expect the next pain test. During the expectation phase, numerous brain regions exhibited activation that was directly related to the magnitude of expected pain. Pain was modulated when the subjects expected decreased pain intensity in 10 out of 10 subjects. A regression analysis confirmed that the decreased expectation of pain accounted for 85% of the variability and that expectation modulated the intensity of the pain experienced both subjectively and by fMRI. These findings showed that expectations of decreased pain produce a reduction of 28.4% for perceived pain. This compares closely with an analgesic dose of morphine (0.08 mg/kg of body weight), which has been shown to reduce pain approximately 25%.³¹

     Two other fMRI blinded clinical experiments9 (N = 23 and N = 24, respectively) using a conditioning design showed that when expectation of pain is heightened, activity in the prefrontal cortex increases; stronger activation in this area has been correlated with greater placebo-induced pain relief and decreased activity within the pain matrix. In a quantitative study by Broadbent et al,^{10 47} adult surgical patients (inguinal hernia repair) were given questionnaires pre- and postsurgery to evaluate stress levels. Stress levels were additionally quantified postsurgically through blood and wound fluid testing. Patient-perceived emotional stress before surgery accounted for 23% of variance in postsurgical pain — greater worry predicted lower levels of matrix metalloproteinase-9 in wound fluid (P = 0.03), greater pain (P = 0.04), poorer self-rated recovery (P = 0.01), and longer recovery time than reported by patients with less stress anticipation. In addition, early wound healing, immune processes, and the inflammatory stage of wound healing were impaired in this group. Specific concern about the operation was more predictive of greater pain and distress after surgery than negative affect (ie, facial expression and posture). This may be due to the attention by this group on the wound and resulting increased attention to signs of pain and discomfort than the less worried group. The authors suggest that interventions to reduce presurgical stress should be considered as a preventive strategy to decrease postoperative complications, including pain, distress, and impaired wound healing. In a randomized controlled clinical trial³¹ of 24 adult patients, relaxation with guided imagery using audiotapes was found to reduce presurgical psychophysiologic stress, anxiety, and postsurgical wound erythema and demonstrated improved healing outcomes.

     Phantom limb pain is closely associated with reorganization of the somatomotor cortex in patients with upper extremity amputation. As mentioned previously, the mouth region has been found to invade the area formerly occupied by the amputated limb and the amount of invasion is closely associated with the magnitude of phantom limb pain.⁴ In addition, the centers in the brain pain matrix have the ability to enhance or block the message. These centers have systemic as well as local effects, including endorphin release, impairment of the inflammatory stage of wound healing, and arousal of the sympathetic nervous system. Thus, “reading” the expression in the patient’s face may be a more accurate reflection of actual pain than only asking for a pain scale number.

     Research has demonstrated that responses are different when pain memories are present. Unlearning pain memories (eg, bandage removal) is very difficult. To achieve this goal, work⁴ is being conducted on retraining the brain rather than treating the body part.

     Historically, war has been a research laboratory for development of new strategies in medicine. Operation Iraqi Freedom and the war in Afghanistan are no exception. Although the technology described is not new, use of continuous catheter-based peripheral nerve blocks (CPNB) has increased in operations on extremities, for perioperative analgesia, and during rehabilitation. In an observational study³² on anesthesia involving 126 war casualties, CPNB was found to provide pain control superior to opioid-based anesthesia. Each patient received a combination of nonsteroidal anti-inflammatory and narcotic analgesics, benzodiazepines, and gabapentin for a mean time of 9 days. Pain scores in patients using indwelling CPNB catheters decreased significantly over 7 days (mean 3.7 ±0.2 to 2.2±0.2, P <0.001). The authors believe that CPNB may have contributed to lower overall pain scores than would have otherwise been observed in this population had patients received standard pain management. The patients included in this study required multiple surgical procedures, serial debridement, and pulsed lavage or were treated with negative pressure therapy (vacuum-assisted closure, KCI, San Antonio, Tex) while receiving CPNB. A review of clinical documentation³¹ showed that patients following this regimen appeared to have less stress related to procedures and faster functional recovery time with fewer side effects than opioid-treated patients. Although this study was conducted in less-than-ideal study conditions, it seems to demonstrate that early intervention with a combination analgesic treatment regimen as described appears to reduce pain significantly. According to the report, a controlled trial in a battlefield setting would not be possible.

     In an observational study,³³ 30 burn patients were assessed for pain using a 100-mm visual analog scale and 4-point verbal pain score before and after a burn dressing change procedure. Nurses (32) and physicians (21) in a burn center developed an analgesic protocol based on anticipated pain intensity during a dressing procedure. Three categories of analgesia were provided to patients before dressing changes and assessed as follows: mild (paracetamo, aspirin, coproxamol and cocodamol — N = 10, 33%); intermediate (DF118, tramadol, and NSAIDs — N = 7, 23.3%); and strong (intramuscular or subcutaneous morphine — N = 1). Six patients (20%) received a combination of the above medications and five patients (16.6%) received nothing. The majority of patients reported satisfactory pain relief with verbal ratings of none or mild pain with mild analgesics in 64% of the procedures. Nurses and physicians anticipated the pain would be moderate or severe and none rated the pain as none or mild; possibly, these clinicians might not have taken into account the change in pain expectation or placebo effect experienced by patients who received an analgesic that may have enhanced the efficacy of the medication administered.

Preventing/Modulating Pain Memories

     The goal of healthcare professionals treating patients should be to provide patient-centered care that will temper pain and reduce pain expectations and painful memories. Clinicians have an opportunity to prevent pain memories using a combination of clinical experience and evidence-based methods that include the following approaches.

     Individualize pain therapy. Pain therapy is not “one size fits all.” Treatment needs to be individualized. The patient may have more than one type of pain (ie, nociceptive wound pain and osteoarthritic pain); plus, response to each type of pain is individual and may need a different treatment approach.³⁴ One strategy is to change the way the patient thinks about pain through education,⁶ such as was seen in the chronic low back pain study. Another would be to change the patient’s pain expectations by using different pain-sparing interventions such as the suggestions to follow.

     Apply an interdisciplinary approach. Best practice wound care is interdisciplinary. No one health discipline has all the tools. Because prevention or modulation of pain messages and improved function, not just pain relief, is the overall goal of care, it is critical that all providers and the patient or caregiver communicate regarding the “fit” of the plan of care.

     Agree on the provider who will prescribe, track, and monitor pain medications, particularly opioids. Only one provider should oversee this function. The patient must know who this is and forge an agreement to use opioid prescriptions only from this one provider.¹¹

     Observe the patient for signs of pain, anxiety, and ease. Clinicians should consider using a faces or distress pain scale to evaluate patient pain. The patient’s affect should be considered for subtle signs or symptoms. The provider should ask him/herself³⁵:
     • Are my patients satisfied with their pain management?
     • Do my patients miss treatment appointments?
     • Do my patients look anxious or cheerful?
     • Do my patients resist wound care?

     Pre-treat for pain or anxiety before clinic visit or procedures. Patients should be encouraged to take pain medication or use a pain-reducing strategy such as relaxation with visual imagery before clinic visits to lower the expectation and reality of pain at the session.

     Choose dressings known to minimize pain. Wound dressing companies have created products that minimize pain and reduce dressing change frequency. Some dressing products incorporate antimicrobial or anti-inflammatory agents in the dressing or are nonadherent to facilitate painless removal.²²

     Choose nonpharmacological interventions.⁹ Nonpharmacological interventions like electrical stimulation have bacteriocidal effects and heal wounds,^36-39 as well as reduce pain.^40,41 Lotze et al²⁴ reported that patients who had upper extremity amputation followed by use of a myoelectric prosthesis did not show somatosensory reorganization and did not develop phantom limb pain. The US Food and Drug Administration allows labeling of electrical stimulation devices for pain applications. Recently published retrospective and case series^42,43 report that low-frequency ultrasound used for wound cleansing is associated with reduced pain.

     Identify and treat infection. Clinicians should be familiar with the clinical characteristics of wound infection. The WUWHS Principles of Best Practice³ is an international initiative to minimize pain during dressing-related procedures through implementation of pain relieving strategies. The document is available online at www.woundpedia.com and includes a table of clinical characteristics of wound infection, one of which is pain.

     To assess for infection, the wound should first be cleansed. Routine and superficial swab wound cultures should be avoided⁴⁴; instead, semiquantitative or quantitative cultures of wound fluid should be performed to identify infectious organisms.^45,46

     Engage, empathize, educate, and enlist the patient.⁴⁷ Patients should be engaged in dialogue about how having a wound and wound-related pain is affecting their quality of life. The clinician may sympathize with how this medical condition has an impact on the patient’s personal self-image and emotions as well as those of significant others. The patient should be encouraged to discuss how pain memories of treatment affect their tolerance for care. Patients and caregivers should be taught how to manage wound pain for improved patient satisfaction. Discussion of the negative effects of treatment regarding pain should be avoided because raising expectation of pain has been shown to induce nocebo, the opposite of placebo, effects that results in hyperalgesia.⁴⁸

     Patient concerns about drug dependency and long-term side effects associated with pain medications must be addressed and clinicians should educate patients about other strategies that prevent and modify pain.26 For example, a randomized blinded study⁴⁹ of patient education in individuals with low back pain did not mention low back pain; instead, the experimental group of 25 patients received 3 hours of education about neurophysiology on pain, including simple anatomy, signal transmission (synapses), neural plasticity, and behavior. The control group of 26 received 3 hours of education about spinal anatomy and physiology that did not include information about nervous system function except for the structural anatomy plus information about biomechanics and exercise. The neurophysiology education group reported reduced pain cognition and improved physical performance posttreatment as measured on several standard pain measurement instruments compared to the control at the 95% confidence interval. Changes were attributed to learning.

     Enlist patient participation. Patients report they like to be actively involved in dressing changes, “the worst part of living with a chronic wound.”^3,50 Thus, patients should be engaged in all treatment planning.

Conclusion

     Until the consequences of wound pain are fully appreciated, healthcare providers will continue to face related challenges as they strive to satisfy patients and heal chronic wounds. The impact of wound-related pain on the development of pain memories, wound treatment outcomes, patients, clinicians, and healthcare systems is reported in the literature. According to this overview of existing evidence on pain, wound pain most likely consists of a combination of local, systemic, and learned phenomena, retained by the patient as long-term pain memories, as well as acute reaction to stimuli. Consideration and evaluation of ways to address these factors can prevent or reduce wound-related pain. Most studies on wound pain deal with pain associated with dressing changes and wound procedures such as sharp and mechanical debridement. Studies about the effect of wound treatment on the development of chronic pain are needed. Functional MRI studies for patients with chronic wounds, by wound type, to evaluate chronic pain effects, including possible regions of brain atrophy and brain reorganization such as those conducted on low back and phantom limb pain, would be useful to test the hypothesis of this paper. At this time, evidence seems to indicate that wound-related pain pathophysiology is similar to other types of chronic pain pathophysiology and information on other types of chronic pain states can be used to guide understanding and treatment decisions about chronic wound pain.

 Dr. Sussman is President, Sussman Physical Therapy/Wound Care Management Services, an education and consulting company. Please address correspondence to: Carrie Sussman, PT, DPT, 3904 W 234 Place, Torrance, CA 90505; email: bcsussman@aol.com.

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