Suspensions for intravenous (IV) injection: a review of development, preclinical and clinical aspects.

There has been growing interest in nanoparticles as an approach to formulate poorly soluble drugs. Besides enhanced dissolution rates, and thereby, improved bioavailability, nanoparticles can also provide targeting capabilities when injected intravenously. The latter property has led to increased research and development activities for intravenous suspensions. The first intravenously administered nanoparticulate product, Abraxane (a reformulation of paclitaxel), was approved by the FDA in 2006. Additional clinical trials have been conducted or are ongoing for multiple other indications such as oncology, infective diseases, and restenosis. This article reviews various challenges associated with developing intravenous nanosuspension dosage forms. In addition, various formulation considerations specific to intravenous nanosuspensions as well as reported findings from various clinical studies have been discussed.

Postsurgical pain outcome assessment.

Reliable and valid measures of pain are essential for conducting clinical trials of pain treatments. Perhaps the most important aspect of a pain measure's validity is its sensitivity, or ability to detect changes in pain over time and due to treatment. Several factors may affect a measure's sensitivity, including the complexity of the rating task for the measure, the number of pain intensity levels assessed by the measure, the dimension of pain assessed (e.g. pain intensity vs. pain relief), and the number of individual ratings (e.g. single rating vs. composite score) used to create the measure. The purpose of this study was to compare the relative sensitivity of three measures of outcome and a composite made up of all three measures for detecting analgesic effects in two samples of persons participating in a randomized controlled trial. One hundred and twenty-three patients who had undergone knee surgery and 124 women who had undergone a laparotomy were given one of three medications in the day after their surgery: morphine, ketorolac, or placebo. Two measures of pain intensity (a visual analog scale (VAS) and a 4-point verbal rating scale (VRS)) were administered at baseline, and these measures plus a 5-point VRS of pain relief were administered at 16 additional time points up to 24 h following surgery. As predicted, we found variability in the sensitivity of the outcome measures used in these studies, with the 4-point VRS showing less sensitivity than the VAS or relief ratings. However, contrary to our prediction, a composite measure of outcome made up of all three measures was not consistently superior to the individual measures for detecting treatment effects. Finally, we found that pain relief ratings were related to, but also distinct from, change in pain intensity as measured by changes in pain intensity ratings from baseline to each postmedication assessment point. These findings have important implications for the assessment of pain in clinical trials.

Lessons learned from a multiple-dose post-operative analgesic trial.

Patients undergoing major surgery often require several days of post-operative analgesic management. However, little data are available on the course of post-operative pain during this period. Such data would be extremely helpful in planning treatment, formulating pain management guidelines, and determining how to construct multiple-dose post-operative analgesic clinical trials. The objectives of this study were to determine (1) if post-operative pain severity, as measured by a modified version of the Brief Pain Inventory (BPI), can be categorized as mild, moderate, or severe in terms of modified BPI pain interference scores, (2) the relationship between modified BPI pain ratings and responses to a categorical item that specifically measures post-sternotomy pain, and (3) the relationship between global ratings of study medication effectiveness and other pain measures. This study is a reanalysis of data from patients who underwent coronary artery bypass graft procedures. We found that the pain severity level cut points developed for chronic pain apply equally well to post-operative pain. Based on this classification scheme, 18% of patients reported moderate pain after day 3, while 14% reported severe pain. Only 9% of patients reported experiencing moderate-to-severe pain approximately 2 weeks later, at the end of the study. Describing pain as mild, moderate, or severe could be a simple, meaningful clinical trial outcome measure. Because most patients experience only mild pain 6 days after surgery, long-term clinical trials of post-operative pain control may be more efficient and cost-effective if they focus on the subset of patients with persistent moderate or severe pain.

Interpretation of visual analog scale ratings and change scores: a reanalysis of two clinical trials of postoperative pain.

The visual analog scale (VAS) is one of the most commonly used measures of pain intensity in pain research. However, there remain important unanswered questions concerning interpretation of specific VAS ratings and change scores. To address these questions, we performed a reanalysis of data from 2 randomized controlled trials of postoperative pain (N = 123 and N = 125) to determine the meaning of VAS pain intensity ratings and change scores. The findings suggested that 100-mm VAS ratings of 0 to 4 mm can be considered no pain; 5 to 44 mm, mild pain; 45 to 74 mm, moderate pain; and 75 to 100 mm, severe pain. As predicted, in assessment of the amount of change corresponding to differing levels of pain relief, percentage change in a patient's VAS score was less biased by pretreatment pain than was absolute change score. The findings also suggested that a 33% decrease in pain represents a reasonable standard for determining that a change in pain is meaningful from the patient's perspective.

The utility and validity of the modified brief pain inventory in a multiple-dose postoperative analgesic trial.

OBJECTIVES: Patients undergoing major surgery often require several days of postoperative analgesia. However, few data exist on the longitudinal course of postoperative pain and the psychometric properties of pain assessment tools used in this setting. Our objective was to validate use of the modified Brief Pain Inventory through reanalysis of pain data from a multiple-dose, placebo-controlled, randomized trial of analgesia after coronary artery bypass graft surgery. METHODS: Four hundred sixty-two patients who underwent coronary artery bypass graft surgery via median sternotomy were administered a shortened form of the original Brief Pain Inventory that contained 3 severity and 5 interference items. Additionally, patients were presented with a single-item measure of procedure-specific pain. Daily pain and interference ratings were available from days 4 to 14 postoperatively. We performed factor analysis to evaluate the consistency with which the modified Brief Pain Inventory items loaded on 2 separate factors corresponding to the original Brief Pain Inventory's pain severity and pain interference subscales. We calculated 2 reliability measures, internal consistency and test-retest reliability, for each subscale. RESULTS: The modified Brief Pain Inventory consistently measured 2 underlying constructs, severity and interference, with Cronbach alphas of 0.85 or greater for the 2 Brief Pain Inventory scales, and test-retest stability coefficients ranging from 0.58 to 0.95 for each pair of consecutive assessment periods. The procedure-specific pain question showed substantial overlap with a general measure of pain severity, suggesting concurrent validity. DISCUSSION: The modified Brief Pain Inventory was stable and valid over the assessment period, suggesting that it can be used during the subacute postoperative period to assess postoperative pain among patients with coronary artery bypass graft surgery.

American pain society pain questionnaire and other pain measures in the assessment of osteoarthritis pain: a pooled analysis of three celecoxib pivotal studies.

The aim of this study was to evaluate the utility of the American Pain Society (APS) questionnaire in the assessment of osteoarthritis (OA) pain and to determine the onset of action of celecoxib in the treatment of acute flare pain in patients with OA of the knee or hip. Pooled data from three pivotal, randomized, double-blind, placebo-controlled, 12-week trials of patients with OA who exhibited a flare of disease activity after withdrawal of nonsteroidal anti-inflammatory drug or analgesic therapy were evaluated. Patients completed the APS Pain Measure Questionnaire, which evaluates pain intensity and quality of life, at baseline and daily for the first 7 days of therapy. In addition, patients underwent a range of standard OA assessments to evaluate the analgesic efficacy of celecoxib up to 12 weeks. Three thousand two hundred fifty-eight patients were enrolled in the three studies, of whom 2041 completed the APS questionnaire (1010 received celecoxib, 513 received naproxen, and 518 received placebo). Within the first 24 hours, celecoxib at a dose of 200 or 400 mg/d significantly reduced the amount of acute pain experienced compared with placebo for four of the five measures, and statistical significance for the remaining parameter, "pain in the last 24 hours," was achieved on day 2. Celecoxib at a dose of 200 to 400 mg/d provided similar efficacy to naproxen at a dose of 1000 mg/d. The pain relief observed with celecoxib was maintained for the APS evaluation period. Long-term efficacy assessments showed the efficacy of 200 mg/d of celecoxib to be continuous and maintained for at least the 12 weeks of the study and that it was equivalent to 400 mg/d of celecoxib and 1000 mg/d of naproxen. This study demonstrates that the APS questionnaire is a useful measure of pain and therapeutic response in OA. Celecoxib furthermore seems to be an effective acute and chronic analgesic in OA.