The Impact of Surgical Amputation and Valproic Acid on Pain and Functional Trajectory: Results from the Veterans Integrated Pain Evaluation Research (VIPER) Randomized, Double-Blinded Placebo-Controlled Trial.

OBJECTIVE: To determine if the perioperative administration of valproic acid reduces the incidence of chronic pain three months after amputation or revision surgery. DESIGN: Multicenter, randomized, double-blind, placebo-controlled trial. SETTING: Academic, military, and veteran medical centers. SUBJECTS: One hundred twenty-eight patients undergoing amputation or amputation revision surgery at Duke University Hospital, Walter Reed National Military Medical Center, or the Durham Veterans Affairs Medical Center for either medical disease or trauma. METHODS: Patients were randomized to placebo or valproic acid for the duration of hospitalization and treated with multimodal analgesic care, including regional anesthetic blockade. Primary outcome was the proportion of patients with chronic pain at three months (average numeric pain score intensity of 3/10 or greater). Secondary outcomes included functional trajectories (assessed with the Brief Pain Inventory short form and the Defense and Veterans Pain Rating Scale). RESULTS: The overall rate of chronic pain was 68.2% in the 107 patients who completed the end point assessment. There was no significant effect of perioperative valproic acid administration, with a rate of 65.45% (N = 36) in the treatment group and a rate of 71.15% (N = 37) in the placebo group. Overall, pain scores decreased from baseline to follow-up (median = -2 on the numeric pain scale). Patients additionally experienced improvements in self-perceived function. CONCLUSIONS: The rate of chronic pain after amputation surgery is not significantly improved with the perioperative administration of valproic acid. In this cohort treated with multimodal perioperative analgesia and regional anesthetic blockade, we observed improvements in both pain severity and function.

Psychometric Testing of the Defense and Veterans Pain Rating Scale (DVPRS): A New Pain Scale for Military Population.

OBJECTIVE: The Defense and Veterans Pain Rating Scale (DVPRS 2.0) is a pain assessment tool that utilizes a numerical rating scale enhanced by functional word descriptors, color coding, and pictorial facial expressions matched to pain levels. Four supplemental questions measure how much pain interferes with usual activity and sleep, and affects mood and contributes to stress. METHODS: Psychometric testing was performed on a revised DVPRS 2.0 using data from 307 active duty service members and Veterans experiencing acute or chronic pain. A new set of facial representations designating pain levels was tested. RESULTS: Results demonstrated acceptable internal consistency reliability (Cronbach's alpha = 0.871) and test-retest reliability (r = 0.637 to r = 0.774) for the five items. Excellent interrater agreement was established for correctly ordering faces depicting pain levels and aligning them on the pain intensity scale (Kendall's coefficient of concordance, W = 0.95 and 0.959, respectively). Construct validity was supported by an exploratory principal component factor analysis and known groups validity testing. Most participants, 70.9%, felt that the DVPRS was superior to other pain rating scales. CONSCLUSION: The DVPRS 2.0 is a reliable and valid instrument that provides standard language and metrics to communicate pain and related outcomes.

Pain Phenotypes and Associated Clinical Risk Factors Following Traumatic Amputation: Results from Veterans Integrated Pain Evaluation Research (VIPER).

OBJECTIVE: To define clinical phenotypes of postamputation pain and identify markers of risk for the development of chronic pain. DESIGN: Cross-sectional study of military service members enrolled 3-18 months after traumatic amputation injury. SETTING: Military Medical Center. SUBJECTS: 124 recent active duty military service members. METHODS: Study subjects completed multiple pain and psychometric questionnaires to assess the qualities of phantom and residual limb pain. Medical records were reviewed to determine the presence/absence of a regional catheter near the time of injury. Subtypes of residual limb pain (somatic, neuroma, and complex regional pain syndrome) were additionally analyzed and associated with clinical risk factors. RESULTS: A majority of enrolled patients (64.5%) reported clinically significant pain (pain score ≥ 3 averaged over previous week). 61% experienced residual limb pain and 58% experienced phantom pain. When analysis of pain subtypes was performed in those with residual limb pain, we found evidence of a sensitized neuroma in 48.7%, somatic pain in 40.8%, and complex regional pain syndrome in 19.7% of individuals. The presence of clinically significant neuropathic residual limb pain was associated with symptoms of PTSD and depression. Neuropathic pain of any severity was associated with symptoms of all four assessed clinical risk factors: depression, PTSD, catastrophizing, and the absence of regional analgesia catheter. CONCLUSIONS: Most military service members in this cohort suffered both phantom and residual limb pain following amputation. Neuroma was a common cause of neuropathic pain in this group. Associated risk factors for significant neuropathic pain included PTSD and depression. PTSD, depression, catastrophizing, and the absence of a regional analgesia catheter were associated with neuropathic pain of any severity.

The expansion and validation of a new upper extremity item bank for the Patient-Reported Outcomes Measurement Information System® (PROMIS).

BACKGROUND: The Patient-Reported Outcomes Measurement Information System® (PROMIS) includes a Physical Function (PF) item bank and an Upper Extremity (UE) item bank, which is composed of a subset of items from the PF bank. The UE item bank has few items and known ceiling effects. Therefore, this study aimed to expand the item bank to assess a wider range of functioning. With the additional content, other psychometric properties-improved content validity, item bank depth, range of measurement, and score reliability-were also evaluated. We convened an expert panel to review potential items, and then conducted psychometric analyses on both extant and newly-collected data. RESULTS: Expert focus groups reviewed the PF item bank for items that were "sufficiently" related to upper extremity functioning for inclusion in the expanded UE item bank. The candidate item bank was quantitatively evaluated in a new sample of 600 people. The final items were calibrated in an aggregated dataset (n = 11,635) from two existing datasets, and the newly collected sample. The original UE item bank included 15 items. After expert review and quantitative evaluation, 31 items were added. The combined 46 items were calibrated using item response theory (IRT). Then computer adaptive tests (CATs) were simulated based off of the psychometric results. These indicated that the new UE item bank has an extended measurement range compared to the original version. CONCLUSIONS: The expanded PROMIS UE item bank assesses a wider range of upper extremity functioning compared to the initial UE item bank. However, ceiling effects remain a concern for unimpaired groups. The new UE item bank is recommended for individuals with known or suspected upper extremity limitations.

Differential expression of systemic inflammatory mediators in amputees with chronic residual limb pain.

Chronic postsurgical pain impacts most amputees, with more than half experiencing neuralgic residual limb pain. The transition from normal acute postamputation pain to chronic residual limb pain likely involves both peripheral and central inflammatory mechanisms. As part of the Veterans Integrated Pain Evaluation Research study, we investigated links between systemic inflammatory mediator levels and chronic residual limb pain. Subjects included 36 recent active duty military traumatic amputees with chronic residual limb pain and 40 without clinically significant pain. Blood samples were obtained and plasma concentrations of an array of inflammatory mediators were analyzed. Residual limb pain intensity and pain catastrophizing were assessed to examine associations with inflammatory mediators. Pro-inflammatory mediators including tumor necrosis factor (TNF)-α, TNF-ß, interleukin (IL)-8, ICAM-1, Tie2, CRP, and SAA were elevated in patients with chronic residual limb pain. Across all patients, residual limb pain intensity was associated positively with levels of several proinflammatory mediators (IL-8, TNF-α, IL-12, TNF-ß, PIGF, Tie2, SAA, and ICAM-1), and inversely with concentrations of the anti-inflammatory mediator IL-13, as well as IL-2 and Eotaxin-3. Pain catastrophizing correlated positively with IL-8, IL-12, TNF-ß, PIGF, and ICAM-1, and inversely with IL-13. Significant associations between catastrophizing and residual limb pain intensity were partially mediated by TNF-α, TNF- ß, SAA, and ICAM-1 levels. Results suggest that chronic postamputation residual limb pain is associated with excessive inflammatory response to injury or to inadequate resolution of the postinjury inflammatory state. Impact of pain catastrophizing on residual limb pain may be because of part to common underlying inflammatory mechanisms.