|Year : 2014 | Volume
| Issue : 1 | Page : 13-21
Postburn pruritus: A practical review
Rajeev B Ahuja1, Pallab Chatterjee2
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 Publication||15-Dec-2014|
Rajeev B Ahuja
Head, Department of Burns & Plastic Surgery, Lok Nayak Hospital and associated Maulana Azad Medical College, New Delhi 110 002
Source of Support: None, Conflict of Interest: None
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
| Introduction|| |
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%. , 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.  Persistence of itching leads to disabling symptoms such as sleep disturbance, anxiety, and disruption of daily activities. 
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. ,,,,, 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|| |
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.  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.  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, , and a state of chronic inflammation,  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.  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. , Most of the studies on itch have been carried on patients with burns ranging from 19% to 24% TBSA,  but itch could be a severe problem in countries showing much higher TBSA of burns,  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  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. ,
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.  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). 
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. , 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). , 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|| |
Pruritus has been broadly classified on the basis of origin of the stimulus. 
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.  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).  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. 
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.  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. ,
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.  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). ,
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. 
| Occurrence of itching in burns: Early itch and late itch|| |
In clinical practice, as well in epidemiological studies, two subtypes of pruritus occur: 
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. , 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.  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. , Thus, during this phase, an aggressive histaminic blockade can be effective in relieving symptoms. 
However, in the later stages of healing, burn wounds appear to become increasingly unresponsive to antihistaminic therapy.  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. 
Why does the efficacy of antihistamines in postburn pruritus decrease with time? Goutos surmises many possible explanations, including but not limited to: 
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. 
| Mechanism of late itch in burns|| |
Goutos believes that the CNS plays a pivotal role in the generation and maintenance of pruritic symptoms in burns patients.  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.  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. , 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.  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. ,, 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. , The same overexpression of neuropeptides is thought to cause increased itching in grafted wounds and hypertrophic scars.  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.  Thus, it is the CNS that develops aberrant autonomous activity that causes maintenance of pruritic symptoms into a chronic state.  Therein lies the potential of centrally acting newer drugs to prevent as well as treat postburn pruruitis.
| Itch assessment|| |
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;  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 , are easy to use, although the data is subjective. These are similar to the more detailed modified McGill pain scale  and the self-reporting seven item questionnaire, the Itch Score Scale. 
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. , 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|| |
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.  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. 
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. , 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.  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.  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. 
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).  Its topical use allows the harness of its significant antihistaminic potency that would produce toxicity with oral dosing.  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.  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 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.  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.  It is likely that their usefulness will be limited to small areas of affected, fully healed skin to avoid systemic toxicity.
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.  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. 
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.  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. 
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. , 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 has been shown to reduce the expression of tumor necrosis factor, interleukin-12 and promote apoptosis in inflammatory cells.  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.  However, the current level of evidence is low.
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.  Unfortunately, no studies are available to provide evidence for the efficacy of this popular preparation in burns patients.
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.  Again, the current level of evidence is low.
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.  This intervention may provide a cost-effective adjunct to troublesome pruritic open burn wounds, but more studies are required to prove its effectiveness.
Pressure therapy has been used for the treatment of hypertrophic scars for over a century.  Studies in adult and pediatric patients have indicated that compression can be an effective measure against burn pruritus, which frequently accompanies active hypertrophic scars.  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.  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. 
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.  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.  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.  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." 
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.  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"  and the effect of increased vagal activity, which reduces circulating stress hormones in treated patients. 
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.  Persistent pruritus was also predicted by submissive personality traits and individuals with less support-seeking attitudes.  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 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.  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. ,
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.  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  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).  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  and 300-900 mg/day in divided doses in adults.  The maximum doses used for epilepsy are 40 mg/kg/day;  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. 
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. 
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. 
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.  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|| |
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.
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