Clinical Research in Practice: The Journal of Clinical Research in Practice: The Journal of Team Hippocrates Team Hippocrates

A clinical decision report using: Gray P

Of the 21 PubMed results, eight were unrelated to the clinical question and immediately excluded. [3][4][5][6][7][8][9][10][11][12][13][14][15] One result was a retrospective cohort study that identified risk factors in developing chronic neuropathic pain following hand burns. 16 Three results investigated pruritis [17][18][19] , a subtype of neuropathic pain often experienced by burn victims. Chung et al. is a review that described the physiologic mechanisms underlying post-burn pruritis 17 , while Foroutan et al. and Ahuja et al. are reviews that investigated the antipruritic effects of pregabalin in burn patients. 18,19 Both aforementioned studies concluded that pregabalin was effective in reducing postburn pruritis. However, because Ms. Grant was not experiencing post-burn pruritis, these articles were excluded.
Kaul et al. was a retrospective chart review that studied the effects of gabapentinoids in reducing pruritis and other forms of neuropathic pain in pediatric burn victims. 20 The authors found gabapentin and pregabalin to be highly efficacious. However, this study was ultimately excluded as it was not a randomized controlled trial, and did not address whether pregabalin would reduce opioid consumption. Additionally, Ms. Grant would not have fit inclusion criteria for this study on the basis of her age.
Wong et al. is another retrospective chart review conducted upon patients experiencing post-burn neuropathic pain. 21 69% of patients who completed the study achieved pain score reduction after three weeks or less of treatment with pregabalin. However, like Kaul et al., this study was also excluded as it was not a randomized controlled trial and did not address the effect of pregabalin on patients' opioid consumption.
The two remaining articles (Jones et al. and Gray et al.) were randomized, double-blind, placebo-controlled studies investigating the efficacy of pregabalin in reducing neuropathic pain and opioid consumption in burn victims. 22,2 Jones et al. was a study conducted on 54 burn patients with a median TBSA affected of 5%. 22 Patients were randomized into three treatment groups: pregabalin 300 mg daily, pregabalin 600 mg daily, and placebo. Post-burn pain levels were measured using the 10-point Visual Analog Scale. Additionally, opioid consumption was recorded either during the first three days of treatment or until the patient was discharged, whichever came first. A statistically significant difference in post-burn pain levels was identified between the Pregabalin 300 and Pregabalin 600 groups. However, the difference in post-burn pain levels between both Pregabalin groups and the placebo group were statistically insignificant. In addition, the difference in opioid consumption between all three groups was statistically insignificant. This study had shortcomings, including a high participant attrition rate following discharge from the hospital and limited data collection following an unanticipated change in the standard of care for burn patients at the investigators' institution, leading to shorter hospitalization periods and decreased enrollment.
The second study, Gray et al., was conducted on 90 burn victims with 5% or greater TBSA affected. 2 Patients experiencing symptoms of neuropathic pain were randomized into two treatment arms, pregabalin or placebo. Patients in the pregabalin group received 75 mg of pregabalin twice daily, which could be up-titrated to 300 mg twice daily if pain scores remained high. Unlike Jones et al., postburn pain levels were measured using the Neuropathic Pain Scale (NPS), an assessment tool that quantified participants' perception of ten neuropathic pain symptoms. This allowed researchers to quantify how "hot" and "sharp" participants' pain felt throughout the study. Gray et al. also studied opioid consumption throughout the 4-week trial.

Critical Appraisal
Gray et al. is a randomized, double-blind, placebo-controlled study investigating the efficacy of pregabalin in reducing neuropathic pain and opioid consumption in burn victims. While the authors did not disclose their source of funding, they declared no conflicts of interest in the design or conduct of the trial. This study qualifies as level of Evidence 1B per SORT criteria. 23 Patients between 18 and 65 years of age who were admitted to the Burn Unit of a large, tertiary referral hospital in Australia were screened for inclusion in the trial. Immediate exclusion criteria included less than 5% TBSA burned, regular use of antiepileptic drugs at the time of the burn injury, neuropathic pain prior to burn injury, administration of intravenous lidocaine or mexiletine after burn injury, allergy to gabapentinoids, and history of psychiatric illness or substance abuse. Patients who were not immediately excluded were subsequently screened for study entry by completing the NPS every day. If a patient rated either "hot pain" or "sharp pain" greater than or equal to 4, they were offered entry into the trial given that they were not pregnant and demonstrated a creatinine clearance greater than or equal to 60 milliliters per minute, liver enzyme levels within normal limits, and an Internationalized Normalized Ratio less than 1.5. Ultimately, 90 patients were enrolled in the trial. Given her past medical history and the quality of her neuropathic symptoms, Ms. Grant would have qualified for enrollment. Information regarding the participants' past medical histories, including chronic pain conditions, was not provided. Most of the study participants were younger than Ms. Grant (mean age of 35.7 with S.D. of 12.8), and most were male (83.3%). The mean TBSA burn for participants was not provided. Like Ms. Grant, 75.5% of participants had burns severe enough to warrant skin grafting.
Participants were randomized into two cohorts for the duration of the 28-day trial. 46 participants entered the pregabalin arm, while 44 participants entered into the placebo arm. The staff and researchers were blinded to the group allocation for the duration of the study. This sample size was sufficient to obtain a significance level of =0.05. Initially, patients received 1 capsule (75 mg pregabalin or placebo) by mouth twice daily. Patients continued on this regimen unless they rated their perception of "sharp pain" or "hot pain" on their daily NPS greater than or equal to 4. If this occurred, their medication was increased to 150 mg pregabalin or placebo twice daily. If they rated their perception of "sharp pain" or "hot pain" greater or equal to 4 on any subsequent day, their medication was increased to the maximum dose of 300 mg pregabalin or placebo twice daily. It should be noted that pain scales including the NPS do not provide an objective measure of pain, as pain considered mild by one participant might be considered severe to another. Additionally, patients completed their daily NPS alongside blinded research nurses, who could have introduced observer bias. After 28 days, medications were weaned and stopped. Primary outcome measures included the "sharp pain" and "hot pain" scores on the NPS. Additional outcomes measured included the remaining elements of the NPS, daily opioid requirement, procedural pain score, side effect profile, and persistence of pain at a 6-month follow-up. The study attempted to maintain a standardized regimen with regard to analgesic administration. However, opioids were administered in various routes depending on patients' individual needs.
As investigators noted, an ideal approach would have been to provide all patients with an intravenous morphine patient-controlled analgesia device for the duration of the 28-day trial. However, this would have been impractical and increased the risk of intravenous line infection. Overall, the pregabalin arm had a 73% retention rate while the placebo arm had a 75% retention rate.
Participants in the pregabalin arm demonstrated statistically significant improvements in sharp and hot pain compared to placebo during the trial (P=0.04 and P=0.01 respectively). Additionally, investigators noted a statistically significant improvement in procedural pain in patients who received pregabalin versus placebo (P=0.02). The average daily Morphine Parenteral Equivalent (MPE) dose for each 7-day period of the trial showed a statistically significant decrease in opioid requirement within either cohort, reflecting patient recovery. However, differences in opioid consumption between the placebo and pregabalin groups were not statistically significant (P>0.05). The difference in frequency of side effects between the pregabalin and placebo groups and persistence of pain 6 months after injury was statistically insignificant.

Clinical Application
Two weeks after sustaining a burn injury, Ms. Grant complained of bothersome sharp and burning sensations in her affected upper extremity, similar to those experienced by participants in Gray et al. Additionally, Ms. Grant was hesitant to continue taking opioid medications, citing unpleasant side effects, as well as risk of developing