Authors: Santiago R1, Gomes S1, Ozsarfati J1, Zitney M1   1Meditech Rehabilitation Centre, 411 Horner Avenue Unit 1 Toronto ON, M8W 4W3   Abstract: Dermatological applications, especially wound healing are accepted indications for Photobiomodulation Therapy. The expansion into other applications, particularly neurologic applications show promise with continuing investigations. We present this case of a patient with a hypertrophic scar and associated severe neuropathic pain and consequent symptoms of depression, whose symptoms improved either directly or indirectly with PBMT. Although the main focus of treatment was dermatological, the improvement in pain and mood symptoms and eventual discontinuation of opioids, antidepressants and benzodiazepines were considered the result of PBMT.   INTRODUCTION: Being the largest organ of the human anatomy and the most superficial, Photobiomodulation Therapy (PBMT) of the integument receives the most attention in terms of coverage. Being a superficial organ allows light therapy to penetrate into most of the layers of the skin. PBMT frequently is used to assist in wound healing and to hasten recovery but also has been shown to improve scar appearance, particularly with hypertrophic scars and keloids. PBMT has also found increased use with regard to neurologic conditions. Both nociceptive and neuropathic pain has been found very responsive to PBMT, and its’ use as an adjunct to treatment of mood disorders is currently being investigated. We present here a patient with a hypertrophic post-surgery scar accompanied by severe Surgically Induced Neuropathic Pain (SNPP), affecting her quality of living and leading to depression, treated with PBMT and eventually improving all three symptoms. CASE PROFILE: The patient on presentation was a 32 year old female who initially presented in Meditech Rehabilitation Centre complaining of an extremely tender and hyperemic abdominal scar. The scar is secondary to an open cholecystectomy performed 2 years prior to initial presentation. A few weeks after her surgery, the patient noted progressive pain in the surgical site but was a fully functional professional. A motorcycle accident led to extreme pain symptoms along the surgical site which continued to presentation. An abdominal ultrasound performed only noted a small amount of thinning of the right anterior abdominal wall with no evidence of herniation. She was unable to work due to severe right upper quadrant pain on motion which was diagnosed as most likely secondary to entrapment of the sensory subcutaneous nerve leading to post-surgical neuropathic pain. At the time of presentation, she was unemployed, mostly homebound, living with and dependent on her parents for support and was unable to travel for short distances or to exercise. Pertinent medical history included a history of colonic inertia, treated with an ileostomy in 2011 followed by a colectomy and an ileo-rectal anastomosis. She underwent an open cholecystectomy two years prior to presentation in 2013 secondary to sludge formation and cholecystitits. The cholecystectomy incision, despite having been fully healed and scarred over since the surgery remains extremely painful to bending forward and backward, movement and occasionally hyperemic. Her family physician described episodes of waking up screaming in extreme, intolerable pain and despite her attempts was unable to return to work. She has since been referred to two surgeons for potential scar revision but was advised against it by both. She was then referred to a pain specialist, who noted defence and pain on the right hypochondrial region to touch and noted tenderness on the lower part of the ribs from T9 to T11 but no noted skin discolouration or pustules. She received multiple epidural and intercostal nerve blocks surrounding the incision scar with only temporary relief of symptoms lasting less than two weeks. On presentation, she was taking Tylenol # 2 (Acetaminophen 300 mg/Codeine 15 mg) 6 pills daily, Escitalopram 10 mg once daily, Dexlansoprazole 60 mg once daily, Ondansetron 4 mg twice daily and 1 mg Lorazepam at bedtime. She has been diagnosed with depression, anxiety, adrenal gland insufficiency and complex pain syndrome by her Family Physician. The patient on presentation had a depressed mood consistent with depression due to a general medical condition.1 She described her pain symptoms as 10/10 on a visual analogue scale within the preceding 24 hours. Physical examination shows moderate distention of the abdomen. On the right upper quadrant there is a linear 15 cm. hypertrophic oblique scar secondary to an open cholecystectomy. The patient has Fitzpatrick Skin type 2. There are noted hematomata and ecchymoses surrounding the abdominal scar accompanied by severe tenderness to touch. The patient describes the pain as severe burning, stabbing and lancinating pain. There is considerable scar tissue over the surgical site and the subcutaneous tissues. There is minimal to moderate tenderness throughout the abdominal wall but is most severe in the right upper quadrant that prevents palpation of the liver. Two other abdominal scars secondary to the previous abdominal surgeries were asymptomatic. The patient agreed to undergo PBMT with every other day treatment covering the cholecystectomy scar using the BIOFLEX® Therapist 240+ system (Meditech International, Inc. Toronto ON) arrays composed of 240 bicolour Light Emitting Diode (LED) array set followed by laser probes (Red AlGaInP Laser max power at 100mW; Infrared GaAlAs Laser max power at 200mW). LED arrays were laid directly over the cholecystectomy scar with full skin contact. Laser probes were directed along the edges of the cholecystectomy scar with only light skin contact as even light pressure in the region triggers severe pain. Initial treatment was provided every other day in Meditech Rehabilitation Centre for 6 weeks, after which a home therapist unit was provided to the patient to continue LED treatment at home. Laser probes were applied once a week in the clinic. At this stage, patient reported 6/10 pain symptoms over 24 hours. The patient continued home treatment three times a week for a period of 2 months, after which she started using the device only as needed. The following parameters were used on initiation: Red LED: 660 nm. Treatment Duration: 360 seconds per placement x 3 placements. Irradiance: 10 mW/cm2. Fluence: 3.6 J/cm2. Infrared LED: 840 nm. Treatment time 360 seconds x 3 placements. Irradiance: 20 mW/cm2. Fluence: 7.2 J/cm2. Red Laser Probe: 660 nm. Treatment Duration: 7 second scattered spot treatment x 10 minutes. Irradiance: 750 mW/cm2per spot treatment. Fluence: 5.25 J/cm2per spot treatment. Infrared Laser Probe: 825 nm. Treatment Duration: 7 second scattered spot treatment x 10 minutes. Irradiance: 1350 mW/cm2per spot treatment. Fluence: 9.45 J/cm2per spot treatment. Parameters were adjusted after every 3 treatments, including pulsing the LED arrays and gradually increasing the pulse frequency. Pulse frequencies and duty cycles were adjusted based on patient input on pain relief, other parameters were maintained. Minimum pulse frequency is at 50 Hz and maximum at 1000 Hz. The patient reported best pain relief between 100 and 250 Hz. Laser diodes were maintained at continuous wave but was only applied once a week in the clinic after the patient initiated self-treatment at home. During follow-up appointments during the next year, the patient noted that the pain in her scar has begun to improve along with scar appearance. Eventually, she slowly decreased her intake of Tylenol #2, Escitalopram and Lorazepam until she discontinued them altogether. The patient reported 4/10 pain symptoms within 24 hours. With the improved appearance of the abdominal scar and decrease in pain symptoms, the patient has also improved with regard to activity. She has begun walking and exercising at home. Mood symptoms have also improved, with decreased anxiety and depression. She has since been advised to only use PBMT as needed for breakout pain. Aside from PBMT, the patient continued to be under the care of a family physician and an endocrinologist for other medical issues. There is an overall improvement in the patients’ outlook in life. She has discontinued opioids for pain and benzodiazepines for sleep and is only taking occasional acetaminophen tablets for breakthrough pain. The patient currently is employed in a full time position and lives independently. Her current pain scale score is 1/10 within 24 hours. She currently continues with occasional maintenance treatment of her hypertrophic scar at a low fluence. DISCUSSION: The treatment of dermatological issues and wound healing is one of the most frequent uses and indications of PBMT. NASA has previously reported on accelerated wound healing in singular atmospheric conditions and submarine conditions using PBMT.2Tissue response to PBMT is due to the energy absorption by certain photo-accepting molecules. Various molecules have been considered to play this role, including melanin, water, as well as chromophores present in microorganisms present in skin, but the biological molecules most responsive to the wavelength we use at 660 nm and 825-840 nm is cytochrome-C oxidase, present in the mitochondria and one of the molecules responsible for the electron transport chain and production of adenosine triphosphate. The reaction involves the production of reactive oxygen species (ROS) that activates nuclear factor-kappa B (NF-kB), a cytoplasmic molecule that signals a cascade which includes wound contraction, inflammation, fibroblast differentiation and collagen deposition.3This may lead to the extracellular activation of transforming growth factor β (TGF-β) which has an effect on a large range of cells in the wound milieu, including hemostasis (platelet-derived TGF-β) and inflammatory cells (macrophage-derived TGF-β) and its prominent role on the extracellular matrix (latent TGF-β–binding protein-associated TGF-β1 sequestered in the matrix). PBMT also has an effect on pain and inflammatory mediators such as histamine, serotonin, bradykinin, and prostaglandins and promotes epithelial migration and proliferation, endothelial migration and organization for angiogenesis, inflammatory infiltration, macrophage phagocytoses, immune surveillance, fibroblast matrix synthesis, and wound contraction.4 Keloids and hypertrophic scars are caused by a dysregulated wound-healing process. These scar types are difficult to eradicate and conventional treatments are not always successful. Keloids or hypertrophic scars could potentially benefit from PBMT by modulating the key cellular features of skin fibrosis. This includes increasing ROS generation, inhibiting fibroblast proliferation without increasing apoptosis, inhibiting collagen production, and inhibiting fibroblast migration speed. Several authors have documented the effect of PBMT in restructuring keloids, the processes most likely are also controlled by TGF-β.5,6 Surgically-Induced Neuropathic Pain (SNPP) as described by Borsook, et al, is “persistent pain estimated to occur in 10–50% of individuals after common operations. It frequently has a delayed onset of months to years after the actual surgery.”7 They described three types of pain typical of SNPP: nociceptive pain, which results from activation of high threshold peripheral sensory neurons as caused by an incision; inflammatory pain due to inflammatory mediators lowering the threshold of nociceptors that innervate the damaged and inflamed tissue, and; neuropathic pain due to nerve injury and is characterized by sensory loss with paradoxical hypersensitivity.7Both nociceptive and inflammatory pain can improve once the offending stimulus settles, in this case after wound healing. But neuropathic pain syndromes, like trigeminal and herpetic neuralgia, tend to be chronic and is due to direct nerve damage. Pain perception is subjective and requires cortical input. While anesthetized during surgery, nociceptive signals are still present activating well-described afferent pathways to multiple brain areas including sensory, emotional, autonomic and modulatory. Inadequate anesthesia leads to the perception of pain. The transformation of nociception into pain, and acute pain into chronic pain is complex and hard to define, but once a nerve is injured an ongoing process unfolds that may be modulated but not easily reversed by current treatments. Even with improved post-operative pain management, intermittent (breakthrough) pain can still lead to a chronic syndrome. Treatment options for chronic pain secondary to SNNP include temporary regional and epidural blocks, continuous analgesic blockade, and medication from simple analgesics to anticonvulsants, antidepressants, and opioids. Unfortunately, treatments for neuropathic pain are not highly effective. Placebo-controlled trials in neuropathic pain suggest approximately 30% efficacy. Because of this, discussions about the possibility of SNPP should be initiated pre-operatively. The CNS manifestations that occur are termed “centralization of pain” and affect sensory, emotional, and other (e.g. cognitive) systems as well as contributing to some of the manifestations of the chronic pain syndrome (e.g., depression and anxiety).7 PBMT can relieve nociceptive pain by partially inhibiting nerve conduction and reducing afferent stimulation, similar to the effect of local anaesthetic injections and used frequently by dentists post-oral surgery. Although current evidence shows that cutaneous application of light acts primarily via peripheral mechanisms and thus only has peripheral analgesic effects (as opposed to visual applications of light treatment which may induce central analgesic effects),8PBMT applied on skin can may not only induce reduced stimulation of peripheral nerve endings but it may also result in reduced synaptic activity with second-order dorsal horn neurons, which in turn modulates the afferent input to higher centers, a term now frequently called neuroplasticity. PBMT also leads to reduced inflammation and the release of endorphins that further provide pain relief.9For the treatment of pain, red and near-infrared wavelengths were administered only cutaneously with a short duration of exposure in seconds to minutes. Although nerve entrapment was not surgically resolved, pain signals most likely were modulated by PBMT. The treatment of neuropathic pain is a bit more complex, as sometimes, overtreatment may actually aggravate pain. Frequently used for other types of neuropathic pain like trigeminal neuralgia and post herpetic neuralgia, oftentimes patients do not continue with treatment due to increased pain after treatment. Pulsed light seems to be effective in modulating this type of pain, and it was demonstrated in this patient. Moore previously applied an 830-nm, 60-mW continuous wave laser for 6–8 minutes immediately following wound closure leading to decreased post-operative drug use in a group of open cholecystectomy patients.10However, we demonstrate here the effectiveness of pulsed modes in modulating chronic pain, with the same result.11 The patients’ occasional maintenance use of PBMT in our opinion is due to this continued modulation of pain signals and there reports of recurrence of symptoms with discontinuation of treatment12 although the placebo effect cannot be totally ruled out. PBMT has also been discussed as a potential tool for treatment of mood disorders, specifically major depression and post-traumatic stress disorder. While proper clinical trials using PBMT specifically for mood disorders are still lacking, several studies have come out supporting its’ use in other neurological disorders like concussions. Affective symptoms like depression are typical for concussions. Several studies have documented the improvement in mood, as well as in other symptoms of concussion like anxiety, sleep difficulties, memory and cognition. It would be assumed the cortical faculties that lead to affective symptoms in concussions are also responsible for mood disorders in general. Most studies investigating PBMT for these conditions usually use the transcranial route.13However, the role of remote PBMT (in this case, potential secondary systemic effects from treatment of the abdominal wall) cannot be ruled out. 14The skin may serve as a neuroendocrine organ and promotes signal exchange with the brain.15 It is possible that specific molecules like nitric oxide (NO) from the body’s largest organ (the skin) can be mobilized with potential beneficial effects.16 The systemic effects of PBMT on mood have been previously reported. Although we cannot directly attribute the improved mood symptoms directly to PBMT and indeed may be secondary only to the improved pain symptoms, previous studies have described the role of remote PBMT in improving certain central nervous system conditions such as Parkinson’s disease by applying PBMT cutaneously in areas distal from the cranium.17 Improving scar tissue appearance, decreasing pain symptoms and knowing that with more mobility you can do more with your life by itself can lead to an improvement in depression symptoms and the placebo effect cannot totally be ruled out. However, the patient’s symptoms have been present years before her initial presentation and maintenance therapy with selective serotonin reuptake inhibitor antidepressants, benzodiazepines and opioids have not addressed her symptoms. PBMT was used in this case mainly for the purpose of improving overall scar appearance. Providing subsequent neuropathic pain relief and consequently, improved mood may indicate a potential for PBMT as treatment for a variety of post-surgical pain syndromes and decrease the reliance on psychotropic medications for these conditions.   Disclosure Statement: No funding was received for this manuscript. RS, SG, and JO are employees of Meditech Rehabilitation Centre and MZ is the medical director of Meditech Rehabilitation Centre. Meditech International is the parent company of Meditech Rehabilitation Centre and the manufacturer of BIOFLEX® devices.   Consent for Publication:   The patient provided written informed consent to have this report published.   Acknowledgement:   We would like to offer acknowledgement to Dr. Fred Kahn, President and CEO of Meditech International who initially supervised and directed treatment.     REFERENCES:
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