Home Print this page Email this page Users Online: 296
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
CME ARTICLE
Year : 2014  |  Volume : 22  |  Issue : 1  |  Page : 13-21

Postburn pruritus: A practical review


1 Department of Burns, Plastic, Maxillofacial and Microvascular Surgery, Lok Nayak Hospital and associated Maulana Azad Medical College, New Delhi, India
2 Now Wing Commander and Classified Specialist (Surgery) and Plastic Surgeon at Command Hospital Air Force, Bengaluru, Karnataka, India

Date of Web Publication15-Dec-2014

Correspondence Address:
Rajeev B Ahuja
Head, Department of Burns & Plastic Surgery, Lok Nayak Hospital and associated Maulana Azad Medical College, New Delhi 110 002
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-653X.146996

Rights and Permissions
  Abstract 

The incidence of postburn pruritus is reported to vary between 80% and 100% and the persistence of itching leads to disabling symptoms such as sleep disturbance, anxiety, and disruption of daily activities. Recently, a few small randomized controlled trials by investigators have focused our attention to the neurobiology and molecular mechanisms of the postburn pruritus and the role of centrally acting agents in its treatment. It is now recognized that the central nervous system develops aberrant autonomous activity that causes maintenance of pruritic symptoms into a chronic state. This practical review on the topic aims to rationalize and simplify the current treatment options, through emerging and available evidence, to enable the physician to make an even better informed choice. While antihistamines and massage therapy will continue to be effective first-line strategy for most clinicians, the promising results in controlled studies obtained with gabapentin/pregabalin to ameliorate pruritic symptoms in a predictable fashion in burns patients have caused a paradigm shift in the therapeutic approach. Tailoring the drug therapy to the severity of symptoms leads to more successful therapy of this vexing malady and current evidence supports the use of gabapentin/pregabalin in patients with moderate to severe postburn pruritus (visual analog scale score >5) as the first line, even if as an "off label" indication. Other treatment modalities like doxepin, ondansetron, or transcutaneous electrical nerve stimulation may have applications on a case to case basis. However, massage therapy should continue to be an adjunct with all other modalities.

Keywords: Antihistamines, early itch, gabapentin, late itch, post burn itch, post burn pruritis, pregabalin


How to cite this article:
Ahuja RB, Chatterjee P. Postburn pruritus: A practical review. Indian J Burns 2014;22:13-21

How to cite this URL:
Ahuja RB, Chatterjee P. Postburn pruritus: A practical review. Indian J Burns [serial online] 2014 [cited 2019 Sep 18];22:13-21. Available from: http://www.ijburns.com/text.asp?2014/22/1/13/146996


  Introduction Top


Postburn itch may be conveniently defined as an unpleasant sensation and desire to scratch the healing/freshly healed burn wound. The incidence of postburn pruritus is reported to vary between 80% and 100%. [1],[2] The presence of itch correlates strongly with factors like healing time since injury (>03 weeks specifically), the percent of total body surface area (TBSA) burned (>40%) and the coping strategies adopted by the patient. [3] Persistence of itching leads to disabling symptoms such as sleep disturbance, anxiety, and disruption of daily activities. [4]

There is a paucity of large-scale randomized controlled trials to assess the optimal therapeutic approach for this distressing symptom. Mostly, this is because no pharmaceutical company has initiated a large-scale study in recent times to evaluate any antipruritic drug. However, there has been a substantial progress in the elucidation of the pathophysiology and especially neurobiology of pruritus in the recent years. The small randomized controlled trials by investigators have led to the development of "off-label" use for some centrally acting agents. [5],[6],[7],[8],[9],[10] This review summarily outlines the current practical understanding of the involved neurologic pathways and the evidence for different management approaches that are commonly employed in burn patients.


  Scope of the problem and clinical correlates Top


Pruritic complaints commence in the early stages of wound healing and their severity tends to diminish with time in most patients. The severity of pruritus is the maximum during the proliferative and remodeling phases of wound healing than the acute phase of injury. [11] Patients often report decreased itch intensity during the day than the night time, presumably because visual and auditory stimulations obstruct the itch impulse, as explained by the "gate theory." Extremity burns of upper and lower limbs are more likely to be symptomatic with distressing itch compared to facial burns. [1] We interpret this to result from early clearance of chemical mediators from the face due to high vascular flow, although this has not been clinically investigated. Since quite often the burn injuries are of mixed depth, the patient starts complaining of itch as soon as superficial to deep dermal burns start healing, even if there are still large areas of full thickness burns that await skin grafting. Conservative management of burn wounds leads to prolonged phase of healing and it has been senior author's experience that such patients complain of severe itch, especially with extensive burns, compared to the patients who undergo primary excision of burn wounds with skin grafting. Prolonged wound healing is associated with extensive deposition of collagen resulting in increased release of histamine, [12],[13] and a state of chronic inflammation, [14] with abundance of other chemical mediators like leukotrienes, neuropeptides, prostaglandins etc., which trigger pruritic impulses to central nervous system (CNS) via selective pathways.

A study has shown that patients tend to have a significant amount of itching within 1-month of sustaining burns, with symptoms peaking at 6 months, and they commence to decline by 1-year of injury. [15] Without doubt, itch is most distressing in the initial healing phase, that is, within 6 months of healing, and its chronicity can extend well beyond 7 years, with almost 44% incidence, albeit diminishing in intensity with time. [3],[16] Most of the studies on itch have been carried on patients with burns ranging from 19% to 24% TBSA, [2] but itch could be a severe problem in countries showing much higher TBSA of burns, [17] because besides intensity the extensive preponderance of itch could render treatment modalities ineffective. Efficacy of all antipruritic therapies needs to be evaluated in this category of patients as well for better objectivity in delivering appropriate therapy. It stands to reason that a larger burn surface area would generate a larger and extensive stimulus for itch. Partial thickness burns, which affect the reticular dermis, itch more intensely [1] due to active collagen remodeling (which can even lead to hypertrophic scarring). On the contrary, the grafted areas itch less as the wound bed is devoid of nerve endings for a long time. [1],[3]

Age and sex of the patient are unlikely to be major determinants of pattern and severity of the itch, even if a study found severe itch in 77% of children compared to 50% in adult burn patients. [1] However, coping strategies to stress may be lower in children and females. A prospective study found that at 3 months postburn, pruritic complaints could be predicted by female sex, TBSA burns and the number of surgical procedures (implying a deep injury component). [2]

In the studies investigating antipruritic therapies or protocols, the efficacy has not even been evaluated on the basis of severity of pruritus. Only recently, in a couple of prospective, randomized studies evaluating the role of newer centrally acting agents, pruritus has been classified on the basis of visual analog scale (VAS) to decide drug dosage. [9],[10] It has been proposed to classify pruritus as mild (VAS score 2-5), moderate (VAS score 6-8) and severe pruritus (VAS score 9-10). [9],[10] Such a classification can help in initiating drug therapy, especially the newer centrally acting drugs, in a more rational manner to the targeted patient sub-population.


  Mechanisms of pruritus Top


Pruritus has been broadly classified on the basis of origin of the stimulus. [18]

1. Central pruritus (neuropathic): Arising from dysfunction in the afferent pathway (e.g., postherpetic pruritus and brain tumors) or resulting from CNS dysfunction itself.

2. Peripheral pruritus (pruritogenic): Originating in the skin, as exemplified in urticarial conditions.

A multitude of pruritogenic molecules are involved in generation of itch including the amine group (histamine, serotonin), proteases (tryptase, mast cell chymase), kinins (bradykinin), calcitonin gene related peptides (CGRP), acetylcholine, opioids, arachidonic acid peroxidation metabolites (eicosanoids, leukotrienes, prostaglandins), neuropeptides (substance P), cytokines (interleukin-2), growth factors (nerve growth factor, neurotrophins 3 and 4), interferons, and tumor necrosis factor α. [19] The peripheral component of the itch sensation is transmitted by C fibers (unmyelinated afferents), which travel via the dorsal horn and also transmit pain, heat, and proprioception. Numerous receptors are present on the C fiber terminals that include Type 1 histamine receptor (H1), the m-opioid receptor, the substance P receptor, neurokinin-1, as well as the newly implicated ones such as proteinase-activated receptor 2 and vanilloid receptor-1 (transient receptor potential vanilloid-1). [19] Keratinocytes themselves act as itch receptors as they release neuropeptides on damage. Scratching further damages keratinocytes, and hence, the itch-scratch-itch cycle is maintained. [20]

Inflammatory mediators such as bradykinin, serotonin, and interleukins may not only be peripheral mediators of itch but also have been demonstrated to acutely sensitize nociceptors so that their responses to external stimulation is facilitated and enhanced. In addition, regulation of gene expression induced by trophic factors like nerve growth factor has been shown to play a major role in persistently increased neuronal sensitivity. [21] Trophic factors also initiate nerve fiber sprouting, and increased intradermal nerve fiber density and high neurotrophin levels have been found in patients with chronic pruritus, which also may contribute to the sensitization of nociceptors. [21],[22]

Many features of central sensitization resemble those that are responsible for memory. Central sensitization is produced not only by increased excitability but also by a reduction in inhibitory transmission due to reduced synthesis or action of inhibitory transmitters and to a loss of inhibitory neurons, which may produce persistent enhancement of sensitivity. [23] Itch can then be evoked in patients even by noxious stimuli that should normally be perceived as painful and should suppress itch, indicating a central mechanism. The similarity of central sensitization for pain to mechanically induced itch sensation in the vicinity of an itching stimulus has been documented. This has led to corresponding terms also for central sensitization for itch (allodynia-alloknesis and punctate hyperalgesia-punctate hyperkinesis). [21],[22]

Thus, there is a complex central interplay of pain and itch, as seen in chronic conditions, when noxious stimuli can lead to abnormal responses. Patients with chronic pruritus will experience an itching sensation and not pain when a painful stimulus such as an electrical stimulus is given. Conversely, patients suffering from chronic pain conditions may experience a paradoxical sensation of burning pain in response to iontophoresed histamine. [24]


  Occurrence of itching in burns: Early itch and late itch Top


In clinical practice, as well in epidemiological studies, two subtypes of pruritus occur: [2]

1. Acute, relating to the period from wound closure to the early remodeling phase of healing and affects the majority of patients,

2. Chronic, which persists in a subgroup of burns victims especially those with deep dermal injuries and early posttraumatic stress disorder (PTSD) symptoms.

How are they different from each other at the molecular level?

The tissue injury present in a burn causes a significant increase of plasma histamine and xanthine oxidase concentrations and local release of eicosanoids, bradykinin, substance P, neurokinin A, and other tachykinins. [25],[26] The released substances bind to C fiber receptors and up-regulate C-fiber activation process, causing the process of itching. In an area of deep dermal burn, a loss of the substance P positive fibers is recorded immediately after the injury that correlates with lack of itching noted initially. 2 weeks postburn injury, the density of substance P positive fibers is noted to be higher than in normal skin, now correlating with the onset of itching in such wounds. [27] This itch during the early phase of healing is caused by mast and inflammatory cell population releasing mediators, especially histamine into a region of increased density of sensitized nerve fibers. [6],[28] Thus, during this phase, an aggressive histaminic blockade can be effective in relieving symptoms. [28]

However, in the later stages of healing, burn wounds appear to become increasingly unresponsive to antihistaminic therapy. [1] As evident by studies on pruritus in general, the role of histamine is likely to be minimal in chronic itching as the H-1 receptors develop tachyphylaxis in response to a sustained stimulus. [29]

Why does the efficacy of antihistamines in postburn pruritus decrease with time? Goutos surmises many possible explanations, including but not limited to: [7]

1. Maybe the studies so far have not identified a more specific mediator, more important than histamine, in an already prolific number of peripheral pruritogens.

2. Pathophysiological mechanisms itself are different from histamine or peripheral pruritogen release.

The superiority of agents acting on the CNS for neuropathic pain for treating postburn pruritus raise the possibility that central/neuropathic mechanisms may be responsible in a similar manner to those involving the sensitization in neuropathic pain models. [2]


  Mechanism of late itch in burns Top


Goutos believes that the CNS plays a pivotal role in the generation and maintenance of pruritic symptoms in burns patients. [7] Though, histamine is a key initiator of impulses predominantly in the initial stages of healing, even in these early stages, agents acting on the CNS dramatically relieves distressing symptoms. These drugs are able to block peripheral signals (including those mediated by histamine) from reaching the CNS. [30] In more advanced stages of rehabilitation, histamine appears to become less important in mediating symptoms especially in burn victims with deep injuries and PTSD symptoms; these patients enter a chronic phase of itch characterized by markedly antihistamine-resistant wounds pointing toward mechanisms relying on a sensitized CNS. [7],[30] It is hypothesized that the pruritic symptoms entering a chronic phase is caused by an injury of a critical number of neurons that produces a maladaptive, abnormal response in the nervous system. [31] This damage to the nerves inflicted from the burn injury/treatment causes deafferentation which leads to an altered summative input to the CNS and causes degeneration of inhibitory CNS neurons, interneuron hypoactivity and disinhibition in descending antinociceptive pathways that collectively set the stage for neuropathic itch. [32],[33],[34] A peripheral overabundant expression of neuropeptides, including nerve growth factor and substance P, as well as up-regulation of calcium channel α2 δ sub-units in the spinal cord, further potentiates the process of CNS sensitization observed in chronic burns. [35],[36] The same overexpression of neuropeptides is thought to cause increased itching in grafted wounds and hypertrophic scars. [37] Their importance in propagating pruritic symptoms is indicated by the fact that they are preferentially expressed in the presence of a deep dermal injury, which is a risk factor for the development of chronic itch. [2] Thus, it is the CNS that develops aberrant autonomous activity that causes maintenance of pruritic symptoms into a chronic state. [7] Therein lies the potential of centrally acting newer drugs to prevent as well as treat postburn pruruitis.


  Itch assessment Top


An effective, sensitive, reliable, and reproducible assessment tool for evaluation of itch and its response to therapy is highly desirable. The simplest tool is the itch related part of the Abbreviated Burn Specific Health Scale; [38] though it shows a high degree of inter-rater reliability, it is limited in the information that it collects. The VAS and the Itch Man Scale [39],[40] are easy to use, although the data is subjective. These are similar to the more detailed modified McGill pain scale [4] and the self-reporting seven item questionnaire, the Itch Score Scale. [41]

At present, there are no techniques in clinical use available that provide us with objective data. The possible objective techniques include the use of perceptual matching of the itch sensation with electrical stimuli of different intensities, the use of magnetic resonance imaging/positron emission tomography to observe neuronal activity in response to exogenous itch, microneurography for assessing C fiber activity, and scratching activity while asleep using an accelerometer. [42],[43] These tools have very limited applicability because they are cumbersome, expensive, research-based, and yield data which may not relate to the patient's experience. We recommend using VAS scoring for evaluation of postburn itch.


  Therapeutic strategies Top


Many investigators like Goutos firmly discriminate burns itching into the acute (inflammatory or pruritogenic) type associated with the early stages of healing and the chronic (or neuropathic) type associated type associated with later stages, when epidermal integrity has been restored. [44] Thus, the treatment in the acute phase is more likely to respond to peripheral pruritic pathways, whereas the treatment during the chronic phase should focus on central pruritic pathways.

Interventions during the acute phase: Targeting peripheral pruritic pathway

Cooling of the wound

0Cooling of the wound by showering/bathing, or the use of topical emollients provides temporary relief for the pruritic wound. Itch is inhibited when a cold object is applied on the involved skin area via A-delta fibers which block the C fiber activation process at both spinal and supra-medullary levels. [45]

Antihistamines

Antihistamines have been the mainstay of pruritus management for decades. First-generation antihistamines (including chlorpheniramine, diphenhydramine, hydroxyzine) bind to histaminic, muscarinic, alpha-adrenergic, and serotonergic receptors, whereas second-generation compounds (including cetirizine) have minimal activity at nonhistaminic receptors. The reduced CNS penetration, a more favorable side effect profile and longer duration of action of the newer agents come at a cost of less efficacy than first-generation antihistaminics in the relieving itch. [46],[47] Even first-generation antihistamines, namely diphenhydramine, hydroxyzine, and chlorpheniramine were found to provide complete relief in only 20% of patients with severe postburn pruritus in one study. [1] In the same study, 60% reported partial and 20% no relief with these agents. Another study found the oral combination of cetirizine and cimetidine (H1 and H2 receptor antagonists) to provide a dramatic improvement in numerical itch scores when compared with the diphenhydramine (H1 receptor antagonist)/placebo group involving patients with partial and full-thickness burns up to 50% TBSA. [28] Loratadine has been found as an effective alternative antihistamine in alleviating pruritus in pediatric burns patients who are refractory to diphenhydramine and/or hydroxyzine therapy. [48]

Topical doxepin

Though doxepin is a tricyclic antidepressant, it has potent histamine receptor blocking properties (50 times more potent than the hydroxyzine and 800 times more potent than diphenhydramine as an antihistamine agent). [49] Its topical use allows the harness of its significant antihistaminic potency that would produce toxicity with oral dosing. [50] Topical doxepin cream has been in use for more than a decade in the western countries.

In a study comparing topical 5% doxepin cream with standard therapy (oral antihistamines, skin moisturizers, and sedatives) on healed pruritic wounds, it was found that pruritus stopped in 55% of patients compared with 10% in the control group. [51] The side effect reported in 15% of the doxepin group patients was somnolence which resolved after 2-3 days, and a localized skin allergy reaction in one participant, which necessitated discontinuation of the treatment. Topical 5% doxepin treatment is recommended to be used in limited, fully healed, and epithelialized pruritic burn wounds not exceeding 20% TBSA.

Local anesthetics

Local anesthetics block sodium channels on neuronal cell membranes and impede the propagation of nerve impulses. The itch and flare reactions associated with histamine release are reduced by pretreatment with lidocaine. [1] This indicates that this interference in the intimate interaction between nerve fibers and mast cells is responsible for the antipruritic action of local anesthetics. A very small study using a eutectic mixture of local anesthetics on pruritic healed burns showed a decrease in the mean number of pruritic episodes and antihistamine breakthrough doses compared with the prestudy controls. [52] It is likely that their usefulness will be limited to small areas of affected, fully healed skin to avoid systemic toxicity.

Colloidal oatmeal

Colloidal oatmeal, used frequently in western countries as over the counter preparation, has been shown to reduce pruritus compared to use of antihistamine preparations in one study, when used as a shower/bathing agent between the 5 th and 7 th day postburn. [41] The mechanism of action may be related to the formation of an occlusive barrier on the skin and hence the maintenance of optimal levels of hydration and pH conditions of the skin. [53]

Capsaicin

Capsaicin, a naturally occurring alkaloid, causes depletion of neuropeptides from peripheral nerves leading to selective, long-lasting depression of C-polymodal nociceptors, thus inhibiting generation of itch signals in the nerve fibers. [54] Conflictingly, one study using topical 0.025% capsaicin cream on 30 patients with healed pruritic wounds revealed no significant effect of the treatment on the efficacy measures, including the degree of symptomatic relief from pruritus and quality-of-life measures. [55]

Laser treatment

A few studies involving both adult and pediatric patients with symptomatic burn scars found sustained relief and benefit with the periodic use of the 585-nm flash lamp-pumped dye laser on scar tenderness, surface texture, and pruritus. [56],[57] Pruritus (VAS 0-10) improved at 1-month and remained improved at 6 and 12 months (P < 0.0001). The mechanism of symptomatic relief in these studies might be related to the inhibitory effect of laser on the microcirculation and pruritogenic chemicals found in scar tissue. Highly vascular scars which are itchy may be relieved of itch as well as erythema with use of pulsed dye laser.

Nanocrystalline silver

Nanocrystalline silver has been shown to reduce the expression of tumor necrosis factor, interleukin-12 and promote apoptosis in inflammatory cells. [58] A case report of five patients treated with nanocrystalline dressings for 2 weeks showed a reduction in the pruritic VAS recordings, raising the possibility of effective adjunct in pruritus management. [59] However, the current level of evidence is low.

Aloe vera

Aloe vera
is widely prescribed by burns specialists for the healed wound. It is known to control histamine release by stabilizing mast cell membranes and has also been reported to inhibit the prostaglandin component of inflammatory reactions. [28] Unfortunately, no studies are available to provide evidence for the efficacy of this popular preparation in burns patients.

Topical dapsone

A small pilot study assessed the effectiveness of topical dapsone in eight patients complaining of disabling pruritus in their healed burn wounds. Over the 2-week study period, 84% of patients reported a significant reduction in their symptoms, whereas the rest had moderate relief from their persistent complaints. No toxic serum dapsone levels were recorded in the study. [60] Again, the current level of evidence is low.

Unna boot

In a study with six pediatric patients exhibiting pruritus in excoriated lower extremity autografts, the group receiving a gauze bandage impregnated with glycerin, zinc oxide, and calamine lotion (Unna boot) reported lower itch scores with better appetite, sleep, and play patterns compared to the group treated with conventional dressings in combination with antihistamines. [61] This intervention may provide a cost-effective adjunct to troublesome pruritic open burn wounds, but more studies are required to prove its effectiveness.

Compression garments

Pressure therapy has been used for the treatment of hypertrophic scars for over a century. [62] Studies in adult and pediatric patients have indicated that compression can be an effective measure against burn pruritus, which frequently accompanies active hypertrophic scars. [63] It has been proposed that the pressure controls collagen synthesis by limiting the supply of oxygen and nutrients to the scar and hence blocking the conversion of fibroblasts into myofibroblasts. [64] The antipruritic mechanism of compression therapy is not clear; it may relate to the reduction of inflammatory cells and mediators at the level of the wound through the effect of extrinsic pressure on the capillary circulation. [65]

Ondansetron

5-hydroxytryptamine (5HT) or serotonin is reported to act peripherally in the pathophysiology of pruritus in a variety of disorders, including uremia and cholestasis. C-fibers that conduct itch sensations are known to be stimulated by 5HT. [19] Blocking the 5HT receptors in patients with itching treated with ondansetron (5HT receptor blocker) yielded greater benefit when compared with antihistamines in a double-blinded, randomized, crossover trial. [8] This trial raises the possible role of serotonin antagonists as a therapeutic approach in postburn pruritus to be validated in future trials.

Interventions during the chronic phase: Targeting central pruritic pathway

Transcutaneous electrical nerve stimulation

Transcutaneous electrical nerve stimulation (TENS) involves the application of controlled, low-voltage electrical impulses to the nervous system via electrodes applied directly onto the skin. A pilot study involving 20 adult burns patients with severe pruritus demonstrated a statistically significant change in the reported VAS compared with placebo over a 3-week period. [66] The mechanism of action of TENS probably relates to the stimulation of rapidly conducting. A fibers, whose impulses close the "gate" to transmission of noxious stimuli carried by the slower. C fibers in accordance with the "gate theory of pain." [67]

Massage therapy

In a study investigating the benefit of massage therapy in 20 burns patients, patients received twice weekly 30-min treatments with cocoa butter over a moderately sized scar tissue area during the remodeling phase of wound healing. The itch along with pain and anxiety ratings showed marked improvement from the first to the last day of the study. [4] Massage with emollients serves to moisturize the newly re-epithelialized skin layer that may be deficient in dermal appendages. Other possible mechanisms explaining the effect of massage therapy include the principles of the "gate theory" [67] and the effect of increased vagal activity, which reduces circulating stress hormones in treated patients. [68]

Psychological support

Involvement of psychologists and psychotherapists early in the care of the burns victim is desirable. Studies have confirmed the high incidence of chronic sensory problems including pruritus in patients many years after the burn injury and the resulting interference with quality-of-life. [16] Persistent pruritus was also predicted by submissive personality traits and individuals with less support-seeking attitudes. [3] Given the presence of clear neuro-anatomical evidence of the behavioral aspect of pruritus, it would seem that psychological support has a fundamental role to play in ameliorating the morbidity of burns-associated pruritus.

Gabapentin

Gabapentin is widely used in the treatment of neuropathic pain. The primary action is on the α2 δ subunit of voltage-gated calcium ion channels in the dorsal horn of spinal cord (where both pain and itch pathways synapse), inhibiting the release of excitatory neurotransmitters like glutamate. [69] It also increases the synthesis of the inhibitory neurotransmitter gamma amino butyric acid (GABA) from glutamate by altering the activity of glutamic acid decarboxylase in neurologic tissues. It secondarily inhibits the release of CGRP and substance P, which are mediators of itching, from primary afferent neurons through a primary increase of GABA in the spinal cord. [69],[70]

A pilot study in 2004 investigated the use of gabapentin in 35 children aged between 6 months and 15 years with healing, intensely pruritic burns wounds unresponsive to chlorpheniramine and trimeprazine. [5] There was marked a reduction in reported itching and a reduction/discontinuation of antihistamine intake. Three children developed behavioral problems and in one, this necessitated discontinuation of gabapentin. At follow-up, it was found that some patients had stopped the drug as early as 4 weeks after starting treatment and others with hypertrophied wounds had taken it for up to 18 months.

Ahuja et al., conducted the first randomized, controlled trial of 20 burns patients each in the three arms [9] in the early remodeling phase (wounds completely healed <1-month postinjury). The three arms were cetirizine, gabapentin, and combination of gabapentin with cetirizine. The study confirmed the superiority of gabapentin to cetirizine in terms of symptomatic benefit. The mean VAS reduction was higher for gabapentin compared to cetirizine (95% vs. 52%, P < 0.01) with the additional benefit of a much faster onset of symptomatic relief (day 3 VAS reduction of 74% vs. 32%; P < 0.01). [9] In addition, in patients receiving a combination of gabapentin and cetirizine, the reduction in VAS was 94%, a response not statistically significant compared to gabapentin monotherapy (P > 0.05). Thus, the hypothetical combination of a centrally acting drug with a peripherally acting agent did not result in any better control of postburn itch than monotherapy with gabapentin. A possible explanation for the ineffectiveness seen with antihistamines may be because of a chronic, antihistamine refractory phase of the pruritus as explained earlier.

For postburn pruritus, gabapentin has been given in doses of 5-10 mg/kg/dose tds in pediatric patients [5] and 300-900 mg/day in divided doses in adults. [9] The maximum doses used for epilepsy are 40 mg/kg/day; [71] thus the dosage used for relief of postburn pruritus are lower and without significant adverse effects. No adverse effect was reported by Ahuja et al. in their study. [9]

Pregabalin

This newer molecule is an analog of gabapentin, with similar purported mechanism of action as detailed above. It exhibits a better pharmacokinetic and pharmacodynamic profile, more potent action, longer duration of action permitting a convenient twice daily dosing and lesser potential side effects. [70]

Gray et al. evaluated pregabalin for severe neuropathic burn injury pain on neuropathic pain scale (NPS). This trial demonstrated a significant improvement in not only the NPS, but also in associated itch. [72]

Ahuja and Gupta published in 2013, a double-blind, randomized, and placebo-controlled study with four arms of 20 patients each as the first trial of pregabalin in postburn itch. [10] The four arms were: Pregabalin, cetirizine with pheniramine maleate (antihistamines only), combination group of pregabalin, cetirizine and pheniramine maleate, and placebo. Massage with coconut oil was integral to all groups. In patients with mild itch (VAS scores 2-5) or moderate itch (VAS scores 6-8), near complete remission of itch was seen in combination group and pregabalin group, where the response was comparable, and close to 95%. This was significantly better response than in antihistaminic combination or "massage alone" groups. Among the patients with severe itch (VAS scores 9-10), combination therapy and pregabalin alone groups had exactly similar decrease in itch scores by day 28 (78.9%). This far exceeded the response in the antihistaminic combination and placebo groups (3.9% and 9.2%, respectively). The authors conclude and offer that moderate to severe pruritus (VAS 6-10) could be treated with a systemic, centrally acting agent like pregabalin or gabapentin to eliminate itch or bring it down to tolerable limits. Patients with mild itch (VAS score 2-5) may be better served with addition of pregabalin, even if massage and antihistaminics can control postburn itch to a reasonable extent because of quicker, predictable and complete response. The authors safely used up to a maximum of 300 mg/day of pregabalin in divided doses in adult patients, which is the minimum dosage used in the treatment of neuropathic pain. This signals a paradigm shift in the treatment of postburn pruritus which is in line with the newer understanding of neurobiology of postburn itch.


  Conclusion Top


A plethora of protocols followed to treat the distressing postburn pruritus are mostly empirical approaches with limited evidence to support their effectiveness. A greater understanding of the molecular mechanisms and neurobiology of pruritus has led to the exploration of new therapeutic avenues. While antihistamines and massage therapy will continue to be effective first-line strategy for most clinicians, the promising results in controlled studies obtained with gabapentin/pregabalin to ameliorate pruritic symptoms in predictable fashion in burns patients have opened a new line of thinking. Tailoring the drug therapy to the severity of symptoms leads to more successful therapy of this vexing malady. Even though gabapentin/pregabalin along with others agents like ondansetron will need validation by larger scale studies to prove their efficacy and establish them in the therapeutic armamentarium, we would not hesitate to initiate the treatment in patients with moderate to severe postburnpruritus (VAS score >5) as the first line, even if as an "off-label" indication. We also acknowledge that gabapentin/pregabalin can be very effective in mild or early pruritus too even if most practitioners would use antihistamines and massage for them. We increasingly identify their efficacy in providing quick and predictable relief in such patients which will also prevent their progression into a chronic, pathological state.

 
  References Top

1.
Vitale M, Fields-Blache C, Luterman A. Severe itching in the patient with burns. J Burn Care Rehabil 1991;12:330-3.  Back to cited text no. 1
    
2.
Van Loey NE, Bremer M, Faber AW, Middelkoop E, Nieuwenhuis MK. Itching following burns: Epidemiology and predictors. Br J Dermatol 2008;158:95-100.  Back to cited text no. 2
    
3.
Willebrand M, Low A, Dyster-Aas J, Kildal M, Andersson G, Ekselius L, et al. Pruritus, personality traits and coping in long-term follow-up of burn-injured patients. Acta Derm Venereol 2004;84:375-80.  Back to cited text no. 3
    
4.
Field T, Peck M, Scd, Hernandez-Reif M, Krugman S, Burman I, et al. Postburn itching, pain, and psychological symptoms are reduced with massage therapy. J Burn Care Rehabil 2000;21:189-93.  Back to cited text no. 4
    
5.
Mendham JE. Gabapentin for the treatment of itching produced by burns and wound healing in children: A pilot study. Burns 2004;30:851-3.  Back to cited text no. 5
    
6.
Santos FX, Arroyo C, García I, Blasco R, Obispo JM, Hamann C, et al. Role of mast cells in the pathogenesis of postburn inflammatory response: Reactive oxygen species as mast cell stimulators. Burns 2000;26:145-7.  Back to cited text no. 6
    
7.
Goutos I. Neuropathic mechanisms in the pathophysiology of burns pruritus: Redefining directions for therapy and research. J Burn Care Res 2013;34:82-93.  Back to cited text no. 7
    
8.
Gross S, Overbaugh R, Jansen R. Ondansetron for treating itch in healing burns. Internet J Pain Symptom Control Palliat Care 2007;5.  Back to cited text no. 8
    
9.
Ahuja RB, Gupta R, Gupta G, Shrivastava P. A comparative analysis of cetirizine, gabapentin and their combination in the relief of post-burn pruritus. Burns 2011;37:203-7.  Back to cited text no. 9
    
10.
Ahuja RB, Gupta GK. A four arm, double blind, randomized and placebo controlled study of pregabalin in the management of post-burn pruritus. Burns 2013;39:24-9.  Back to cited text no. 10
    
11.
Goutos I. Burns pruritus - A study of current practices in the UK. Burns 2010;36:42-8.   Back to cited text no. 11
    
12.
Kahlson G, Rosengren E. New approaches to the physiology of histamine. Physiol Rev 1968;48:155-96.  Back to cited text no. 12
    
13.
Phillips LG, Robson MC. Pruritus in burns. Comments from Detroit Receiving Hospital, Detroit, Michigan. J Burn Care Rehabil 1988;9:308-9.  Back to cited text no. 13
    
14.
Demling R, DeSanti L. Topical doxepin significantly decreases itching and erythema in the chronically pruritic burn scar. Wounds 2003;15:195-200.  Back to cited text no. 14
    
15.
Ahee AM, Smith SJ, Pliska-Matyshak G, Cullen ML. When does itching start and stop post-burn? J Burn Care Rehabil 1999;20:S187.  Back to cited text no. 15
    
16.
Malenfant A, Forget R, Papillon J, Amsel R, Frigon JY, Choinière M. Prevalence and characteristics of chronic sensory problems in burn patients. Pain 1996;67:493-500.  Back to cited text no. 16
    
17.
Ahuja RB, Bhattacharya S. An analysis of 11,196 burn admissions and evaluation of conservative management techniques. Burns 2002;28:555-61.  Back to cited text no. 17
    
18.
Bernhard JD. Itch and pruritus: What are they, and how should itches be classified? Dermatol Ther 2005;18:288-91.  Back to cited text no. 18
    
19.
Yosipovitch G, Greaves M, Schmelz M. Itch. Lancet 2003;361:690-4.  Back to cited text no. 19
    
20.
Andoh T, Nishikawa Y, Yamaguchi-Miyamoto T, Nojima H, Narumiya S, Kuraishi Y. Thromboxane A2 induces itch-associated responses through TP receptors in the skin in mice. J Invest Dermatol 2007;127:2042-7.  Back to cited text no. 20
    
21.
Ikoma A, Rukwied R, Ständer S, Steinhoff M, Miyachi Y, Schmelz M. Neurophysiology of pruritus: Interaction of itch and pain. Arch Dermatol 2003;139:1475-8.  Back to cited text no. 21
    
22.
Ständer S, Steinhoff M, Schmelz M, Weisshaar E, Metze D, Luger T. Neurophysiology of pruritus: Cutaneous elicitation of itch. Arch Dermatol 2003;139:1463-70.  Back to cited text no. 22
    
23.
Oaklander AL. Neuropathic itch. Semin Cutan Med Surg 2011;30:87-92.  Back to cited text no. 23
    
24.
Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjork HE, Handwerker HO. Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J Neurophysiol 2003;89:2441-8.  Back to cited text no. 24
    
25.
Lindblom L, Cassuto J, Yregård L, Tarnow P, Räntfors J, Löwhagen Hendén P. Role of vasoactive intestinal polypeptide in burn-induced oedema formation. Burns 2000;26:443-8.  Back to cited text no. 25
    
26.
Löfgren O, Qi Y, Lundeberg T. Inhibitory effects of tachykinin receptor antagonists on thermally induced inflammatory reactions in a rat model. Burns 1999;25:125-9.  Back to cited text no. 26
    
27.
Dunnick CA, Gibran NS, Heimbach DM. Substance P has a role in neurogenic mediation of human burn wound healing. J Burn Care Rehabil 1996;17:390-6.  Back to cited text no. 27
    
28.
Baker RA, Zeller RA, Klein RL, Thornton RJ, Shuber JH, Marshall RE, et al. Burn wound itch control using H1 and H2 antagonists. J Burn Care Rehabil 2001;22:263-8.  Back to cited text no. 28
    
29.
Ko MC. Veiwpoint. 2. How best to fight that nasty itch-from new insights into the neuroimmunological, neuroendocrine, and neurophysiological bases of pruritus to novel therapeutic approaches. Exp Dermatol 2005;14:227-9.  Back to cited text no. 29
    
30.
Goutos I, Eldardiri M, Khan AA, Dziewulski P, Richardson PM. Comparative evaluation of antipruritic protocols in acute burns. The emerging value of gabapentin in the treatment of burns pruritus. J Burn Care Res 2010;31:57-63.  Back to cited text no. 30
    
31.
Sabel BA. Unrecognised potential of surviving neurones: Within systems plasticity, recovery of function, and the hypothesis of minimal residual structure. Neuroscientist 1997;3:366-70.  Back to cited text no. 31
    
32.
Ward RS, Saffle JR, Schnebly WA, Hayes-Lundy C, Reddy R. Sensory loss over grafted areas in patients with burns. J Burn Care Rehabil 1989;10:536-8.  Back to cited text no. 32
    
33.
Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol 2001;429:23-37.  Back to cited text no. 33
    
34.
Porreca F, Ossipov MH, Gebhart GF. Chronic pain and medullary descending facilitation. Trends Neurosci 2002;25:319-25.  Back to cited text no. 34
    
35.
Ward RS, Tuckett RP, English KB, Johansson O, Saffle JR. Substance P axons and sensory threshold increase in burn-graft human skin. J Surg Res 2004;118:154-60.  Back to cited text no. 35
    
36.
Li CY, Song YH, Higuera ES, Luo ZD. Spinal dorsal horn calcium channel alpha2delta-1 subunit upregulation contributes to peripheral nerve injury-induced tactile allodynia. J Neurosci 2004;24:8494-9.  Back to cited text no. 36
    
37.
Crowe R, Parkhouse N, McGrouther D, Burnstock G. Neuropeptide-containing nerves in painful hypertrophic human scar tissue. Br J Dermatol 1994;130:444-52.  Back to cited text no. 37
    
38.
Munster AM, Horowitz GL, Tudahl LA. The abbreviated burn-specific health scale. J Trauma Inj Infect Crit Care 1987;27:425-8.  Back to cited text no. 38
    
39.
Herndon DN. Total Burn Care. Philadelphia: Saunders Elsevier; 2007. p. 802.  Back to cited text no. 39
    
40.
Ratcliff SL, Brown A, Rosenberg L, Rosenberg M, Robert RS, Cuervo LJ, et al. The effectiveness of a pain and anxiety protocol to treat the acute pediatric burn patient. Burns 2006;32:554-62.  Back to cited text no. 40
    
41.
Matheson JD, Clayton J, Muller MJ. The reduction of itch during burn wound healing. J Burn Care Rehabil 2001;22:76-81.  Back to cited text no. 41
    
42.
Yosipovitch G. Assessment of itch: More to be learned and improvements to be made. J Invest Dermatol 2003;121:xiv-xv.  Back to cited text no. 42
    
43.
Bringhurst C, Waterston K, Schofield O, Benjamin K, Rees JL. Measurement of itch using actigraphy in pediatric and adult populations. J Am Acad Dermatol 2004;51:893-8.  Back to cited text no. 43
    
44.
Goutos I. Comment on scratching the surface-managing the itch associated with burns: A review of current knowledge. Burns 2009;35:754-5.  Back to cited text no. 44
    
45.
Biró T, Ko MC, Bromm B, Wei ET, Bigliardi P, Siebenhaar F, et al. How best to fight that nasty itch - from new insights into the neuroimmunological, neuroendocrine, and neurophysiological bases of pruritus to novel therapeutic approaches. Exp Dermatol 2005;14:225-40.  Back to cited text no. 45
    
46.
Simons FE. Advances in H1-antihistamines. N Engl J Med 2004;351: 2203-17.  Back to cited text no. 46
    
47.
Simons FE. H1-Antihistamines: More relevant than ever in the treatment of allergic disorders. J Allergy Clin Immunol 2003;112:S42-52.  Back to cited text no. 47
    
48.
Tager K, Jenkins M, Savlors R, Warden GD. The use of Claritin to control itching in thermally injured patients. J Burn Care Rehabil 1998;19:S261.  Back to cited text no. 48
    
49.
Bernstein JE, Whitney DH, Soltani K. Inhibition of histamine-induced pruritus by topical tricyclic antidepressants. J Am Acad Dermatol 1981;5:582-5.  Back to cited text no. 49
    
50.
Drake LA, Fallon JD, Sober A. Relief of pruritus in patients with atopic dermatitis after treatment with topical doxepin cream. The Doxepin study group. J Am Acad Dermatol 1994;31:613-6.  Back to cited text no. 50
    
51.
Demling R, DeSanti L. Topical doxepin significantly decreases itching and erythema in the healed burn wound. Wounds 2001;13:210-5.  Back to cited text no. 51
    
52.
Kopecky EA, Jacobson S, Bch MB, Hubley P, Palozzi L, Clarke HM, et al. Safety and pharmacokinetics of EMLA in the treatment of postburn pruritus in pediatric patients: A pilot study. J Burn Care Rehabil 2001;22:235-42.  Back to cited text no. 52
    
53.
Kurtz ES, Wallo W. Colloidal oatmeal: History, chemistry and clinical properties. J Drugs Dermatol 2007;6:167-70.  Back to cited text no. 53
    
54.
Hercogová J. Topical anti-itch therapy. Dermatol Ther 2005;18:341-3.  Back to cited text no. 54
    
55.
Choiniere M, Papillon J. Topical capsaicin treatment for post-burn pruritus: A double blind study. In: Abstract: 9 th Congress of the International Society for Burn Injuries; 2001.  Back to cited text no. 55
    
56.
Allison KP, Kiernan MN, Waters RA, Clement RM. Pulsed dye laser treatment of burn scars. Alleviation or irritation? Burns 2003;29:207-13.  Back to cited text no. 56
    
57.
Gaida K, Koller R, Isler C, Aytekin O, Al-Awami M, Meissl G, et al. Low level laser therapy - A conservative approach to the burn scar? Burns 2004;30: 362-7.  Back to cited text no. 57
    
58.
Dunn K, Edwards-Jones V. The role of Acticoat with nanocrystalline silver in the management of burns. Burns 2004;30 Suppl 1:S1-9.  Back to cited text no. 58
    
59.
Brooks P, Phang KL, Moazzam A. Nanocrystalline silver (Acticoat) for itch relief in the burns patient. ANZ J Surg 2007;77:797.  Back to cited text no. 59
    
60.
Bauling PC, McDermott T, Peterson VM. A pilot study on topical dapsone application to decrease itching in healed burn wounds. J Burn Care Rehabil 2002;23:S55.  Back to cited text no. 60
    
61.
Barone CM, Mastropieri CJ, Peebles R, Mitra A. Evaluation of the Unna boot for lower-extremity autograft burn wounds excoriated by pruritus in pediatric patients. J Burn Care Rehabil 1993;14:348-9.  Back to cited text no. 61
    
62.
Leung PC, Ng M. Pressure treatment for hypertrophic scars resulting from burns. Burns 1980;6:244-50.  Back to cited text no. 62
    
63.
Klöti J, Pochon JP. Conservative treatment using compression suits for second and third degree burns in children. Burns Incl Therm Inj 1982;8:180-7.  Back to cited text no. 63
    
64.
Macintyre L, Baird M. Pressure garments for use in the treatment of hypertrophic scars - A review of the problems associated with their use. Burns 2006;32:10-5.  Back to cited text no. 64
    
65.
Wienert V. Compression treatment after burns. Curr Probl Dermatol 2003;31:108-13.  Back to cited text no. 65
    
66.
Hettrick HH, O'Brien K, Laznick H, Sanchez J, Gorga D, Nagler W, et al. Effect of transcutaneous electrical nerve stimulation for the management of burn pruritus: A pilot study. J Burn Care Rehabil 2004;25:236-40.  Back to cited text no. 66
    
67.
Melzack R, Wall PD. Pain mechanisms: A new theory. Science 1965;150:971-9.  Back to cited text no. 67
    
68.
Field T, Peck M, Krugman S, Tuchel T, Schanberg S, Kuhn C, et al. Burn injuries benefit from massage therapy. J Burn Care Rehabil 1998;19:241-4.  Back to cited text no. 68
    
69.
Bennett MI, Simpson KH. Gabapentin in the treatment of neuropathic pain. Palliat Med 2004;18:5-11.  Back to cited text no. 69
    
70.
Fehrenbacher JC, Taylor CP, Vasko MR. Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain 2003;105:133-41.  Back to cited text no. 70
    
71.
Shapiro D, Nordii D, Glauser T. Gabapentin as an add-on therapy for refractory partial seizures in children 1-36 months of age: A novel, short-term placebo-controlled trial. Epilepsia 2000;41(Suppl. 7):106.  Back to cited text no. 71
    
72.
Gray P, Kirby J, Smith MT, Cabot PJ, Williams B, Doecke J, et al. Pregabalin in severe burn injury pain: A double-blind, randomised placebo-controlled trial. Pain 2011;152:1279-88.  Back to cited text no. 72
    



This article has been cited by
1 Post burn pruritus in pediatric burn patients
Sophie Maria Pierrette Nieuwendijk,Iris Johanne de Korte,Mereille Marren Pursad,Monique van Dijk,Heinz Rode
Burns. 2018;
[Pubmed] | [DOI]
2 Management of acute pain in extensive burn injury
Luz Elena Cáceres-Jerez,Omar Fernando Gomezese-Ribero,Laura Isabel Reyes-Cárdenas,Julián Andrés Vera-Campos,Valentina Alejandra Guzmán-Rueda,Juan Pablo Azar-Villalobos,Héctor Julio Meléndez-Flórez
Colombian Journal of Anesthesiology. 2018; 46(1): 49
[Pubmed] | [DOI]
3 The effects of Arnebia euchroma ointment on second-degree burn wounds: a randomized clinical trial
Ebrahim Nasiri,Seyed Jalal Hosseinimehr,Ahmad Zaghi Hosseinzadeh,Mohammad Azadbakht,Jafar Akbari,Masoud Azadbakht
Journal of Ethnopharmacology. 2016; 189: 107
[Pubmed] | [DOI]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Scope of the pro...
Mechanisms of pr...
Mechanism of lat...
Itch assessment
Therapeutic stra...
Conclusion
Occurrence of it...
References

 Article Access Statistics
    Viewed5823    
    Printed137    
    Emailed1    
    PDF Downloaded363    
    Comments [Add]    
    Cited by others 3    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]