Elevated tumor LDLR expression accelerates LDL cholesterol-mediated breast cancer growth in mouse models of hyperlipidemia.

Obesity is associated with an increase in cancer-specific mortality in women with breast cancer. Elevated cholesterol, particularly low-density lipoprotein cholesterol (LDL-C), is frequently seen in obese women. Here, we aimed to determine the importance of elevated circulating LDL, and LDL receptor (LDLR) expression in tumor cells, on the growth of breast cancer using mouse models of hyperlipidemia. We describe two novel immunodeficient mouse models of hyperlipidemia (Rag1-/-/LDLR-/- and Rag1-/-/ApoE (apolipoprotein E)-/- mice) in addition to established immunocompetent LDLR-/- and ApoE-/- mice. The mice were used to study the effects of elevated LDL-C in human triple-negative (MDA-MB-231) and mouse Her2/Neu-overexpressing (MCNeuA) breast cancers. Tumors derived from MCNeuA and MDA-MB-231 cells had high LDLR expression and formed larger tumors in mice with high circulating LDL-C concentrations than in mice with lower LDL-C. Silencing the LDLR in the tumor cells led to decreased growth of Her2/Neu-overexpressing tumors in LDLR-/- and ApoE-/- mice, with increased Caspase 3 cleavage. Additionally, in vitro, silencing the LDLR led to decreased cell survival in serum-starved conditions, associated with Caspase 3 cleavage. Examining publically available human data sets, we found that high LDLR expression in human breast cancers was associated with decreased recurrence-free survival, particularly in patients treated with systemic therapies. Overall, our results highlight the importance of the LDLR in the growth of triple-negative and HER2-overexpressing breast cancers in the setting of elevated circulating LDL-C, which may be important contributing factors to the increased recurrence and mortality in obese women with breast cancer.

Silencing vimentin expression decreases pulmonary metastases in a pre-diabetic mouse model of mammary tumor progression.

Increased breast cancer risk and mortality has been associated with obesity and type 2 diabetes (T2D). Hyperinsulinemia, a key factor in obesity, pre-diabetes and T2D, has been associated with decreased breast cancer survival. In this study, a mouse model of pre-diabetes (MKR mouse) was used to investigate the mechanisms through which endogenous hyperinsulinemia promotes mammary tumor metastases. The MKR mice developed larger primary tumors and greater number of pulmonary metastases compared with wild-type (WT) mice after injection with c-Myc/Vegf overexpressing MVT-1 cells. Analysis of the primary tumors showed significant increase in vimentin protein expression in the MKR mice compared with WT. We hypothesized that vimentin was an important mediator in the effect of hyperinsulinemia on breast cancer metastasis. Lentiviral short hairpin RNA knockdown of vimentin led to a significant decrease in invasion of the MVT-1 cells and abrogated the increase in cell invasion in response to insulin. In the pre-diabetic MKR mouse, vimentin knockdown led to a decrease in pulmonary metastases. In vitro, we found that insulin increased pAKT, prevented caspase 3 activation, and increased vimentin. Inhibiting the phosphatidylinositol 3 kinase/AKT pathway, using NVP-BKM120, increased active caspase 3 and decreased vimentin levels. This study is the first to show that vimentin has an important role in tumor metastasis in vivo in the setting of pre-diabetes and endogenous hyperinsulinemia. Vimentin targeting may be an important therapeutic strategy to reduce metastases in patients with obesity, pre-diabetes or T2D.

The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer.

Estrogen receptor-α (ERα)-negative breast cancer is clinically aggressive and does not respond to conventional hormonal therapies. Strategies that lead to re-expression of ERα could sensitize ERα-negative breast cancers to selective ER modulators. FTY720 (fingolimod, Gilenya), a sphingosine analog, is the Food and Drug Administration (FDA)-approved prodrug for treatment of multiple sclerosis that also has anticancer actions that are not yet well understood. We found that FTY720 is phosphorylated in breast cancer cells by nuclear sphingosine kinase 2 and accumulates there. Nuclear FTY720-P is a potent inhibitor of class I histone deacetylases (HDACs) that enhances histone acetylations and regulates expression of a restricted set of genes independently of its known effects on canonical signaling through sphingosine-1-phosphate receptors. High-fat diet (HFD) and obesity, which is now endemic, increase breast cancer risk and have been associated with worse prognosis. HFD accelerated the onset of tumors with more advanced lesions and increased triple-negative spontaneous breast tumors and HDAC activity in MMTV-PyMT transgenic mice. Oral administration of clinically relevant doses of FTY720 suppressed development, progression and aggressiveness of spontaneous breast tumors in these mice, reduced HDAC activity and strikingly reversed HFD-induced loss of estrogen and progesterone receptors in advanced carcinoma. In ERα-negative human and murine breast cancer cells, FTY720 reactivated expression of silenced ERα and sensitized them to tamoxifen. Moreover, treatment with FTY720 also re-expressed ERα and increased therapeutic sensitivity of ERα-negative syngeneic breast tumors to tamoxifen in vivo more potently than a known HDAC inhibitor. Our work suggests that a multipronged attack with FTY720 is a novel combination approach for effective treatment of both conventional hormonal therapy-resistant breast cancer and triple-negative breast cancer.

Mammary tumor growth and pulmonary metastasis are enhanced in a hyperlipidemic mouse model.

Dyslipidemia has been associated with an increased risk for developing cancer. However, the implicated mechanisms are largely unknown. To explore the role of dyslipidemia in breast cancer growth and metastasis, we used the apolipoprotein E (ApoE) knockout mice (ApoE(-/-)), which exhibit marked dyslipidemia, with elevated circulating cholesterol and triglyceride levels in the setting of normal glucose homeostasis and insulin sensitivity. Non-metastatic Met-1 and metastatic Mvt-1 mammary cancer cells derived from MMTV-PyVmT/FVB-N transgenic mice and c-Myc/vegf tumor explants respectively, were injected into the mammary fat pad of ApoE(-/-) and wild-type (WT) females consuming a high-fat/high-cholesterol diet and tumor growth was evaluated. ApoE(-/-) mice exhibited increased tumor growth and displayed a greater number of spontaneous metastases to the lungs. Furthermore, intravenous injection of Mvt-1 cells resulted in a greater number of pulmonary metastases in the lungs of ApoE(-/-) mice compared with WT controls. To unravel the molecular mechanism involved in enhanced tumor growth in ApoE(-/-) mice, we studied the response of Mvt-1 cells to cholesterol in vitro. We found that cholesterol increased Akt(S473) phosphorylation in Mvt-1 cells as well as cellular proliferation, whereas cholesterol depletion in the cell membrane abrogated Akt(S473) phosphorylation induced by exogenously added cholesterol. Furthermore, in vivo administration of BKM120, a small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), alleviated dyslipidemia-induced tumor growth and metastasis in Mvt-1 model with a concomitant decrease in PI3K/Akt signaling. Collectively, we suggest that the hypercholesterolemic milieu in the ApoE(-/-) mice is a favorable setting for mammary tumor growth and metastasis.

Inhibiting PI3K reduces mammary tumor growth and induces hyperglycemia in a mouse model of insulin resistance and hyperinsulinemia.

Women with type 2 diabetes mellitus (T2DM) are at a greater risk of developing and dying from breast cancer than women without T2DM. Insulin resistance and hyperinsulinemia underlie the pathogenesis of T2DM. In the MKR mouse model of insulin resistance, we have previously shown increased activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway in association with accelerated mammary tumor growth. In this study, we demonstrate that inhibiting PI3K with the oral pan-class I PI3K inhibitor, NVP-BKM120 reduced the growth of Met-1 and MCNeuA mammary tumor orthografts in the MKR mouse. NVP-BKM120 treatment decreased phosphorylation of Akt and S6 ribosomal protein (S6rp); no change in Erk1/2 phosphorylation was seen. Hyperglycemia, hypertriglyceridemia and greater hyperinsulinemia developed in the MKR mice treated with NVP-BKM120. We previously reported reduced tumor growth using intraperitoneal rapamycin in the MKR mouse, with the development of hyperglycemia and hypertriglyceridemia. Therefore, we examined whether the oral PI3K/mTOR inhibitor NVP-BEZ235 augmented the tumor suppressing effects of PI3K inhibition. We also investigated the effect of targeted PI3K/mTOR inhibition on PI3K/Akt/mTOR and Erk1/2 signaling, and the potential effects on glycemia. NVP-BEZ235 suppressed the growth of Met-1 and MCNeuA tumor orthografts, and decreased Akt and S6rp phosphorylation, despite increased Erk1/2 phosphorylation in Met-1 orthografts of MKR mice. Less marked hyperglycemia and hyperinsulinemia developed with NVP-BEZ235 than NVP-BKM120. Overall, the results of this study demonstrated that inhibiting PI3K/Akt/mTOR signaling with the oral agents NVP-BKM120 and NVP-BEZ235 decreased mammary tumor growth in the hyperinsulinemic MKR mouse. Inhibiting PI3K alone led to more severe metabolic derangement than inhibiting both PI3K and mTOR. Therefore, PI3K may be an important target for the treatment of breast cancer in women with insulin resistance. Monitoring for hyperglycemia and dyslipidemia should be considered when using these agents in humans, given the metabolic changes detected in this study.

Resolution of insulin-requiring diabetes in a liver transplant recipient after treatment of a pheochromocytoma: case report and review of literature.

The aim of this paper was to report the case of type 2 diabetes and significant insulin resistance that improved dramatically after removal of a pheochromocytoma in a liver transplant recipient , and to provide a review of the relevant literature. We describe the clinical presentation, diagnostic results and management of the patient. In addition, we performed a PubMed search for related English language articles, to provide an overview of the pertinent literature. A 53 year old woman with a history of an orthotopic liver transplantation and insulin-requiring type 2 diabetes was admitted to the hospital with fever, diaphoresis, tachycardia and hypertension. A pheochromocytoma was diagnosed and removed. The patient subsequently developed hypoglycemia and required no further insulin therapy. Pheochromocytomas have been described to lead to hyperglycemia and diabetes, due to the suppression of insulin release and increased insulin resistance. Furthermore, a review of the literature revealed only 3 other reported cases of pheochromocytomas in organ transplant recipients. None of these pheochromocytomas were believed to have occurred de novo after transplantation. This is the first report of a pheochromocytoma in a liver transplant recipient and possibly the first case of a de novo pheochromocytoma in any organ transplant recipient. Moreover, this case showcases pheochromocytomas as a rare cause of diabetes mellitus.

Obesity and type 2 diabetes are associated with an increased risk of developing cancer and a worse prognosis; epidemiological and mechanistic evidence.

Both obesity and Type 2 diabetes are independently associated with an increased risk of developing cancer and an increased mortality. The etiology is yet to be determined but insulin resistance and hyperinsulinemia maybe important factors. Hyperglycemia, hyperlipidemia and inflammatory cytokines in addition to the insulin-like growth factors are also possible factors involved in the process.

A randomized placebo-controlled trial of single-dose IM corticosteroid for radicular low back pain.

STUDY DESIGN: A randomized, double-blind, placebo-controlled trial of patients with radicular low back pain who present to an emergency department (ED) within 1 week of pain onset. OBJECTIVE: We hypothesized that a single intramuscular 160 mg dose of methylprednisolone acetate would improve pain and functional outcomes 1 month after ED discharge if the corticosteroid were administered early in disease symptomotology. SUMMARY OF BACKGROUND DATA: Parenteral corticosteroids are not recommended for acute, radicular low back pain, though their role in this disease process is ill-defined. To date, this medication class has only been studied in a highly selected group of patients requiring hospitalization. METHODS.: Adults between the ages of 21 and 50 who presented to an ED with low back pain and a positive straight leg raise test were enrolled. The primary outcome was change in pain intensity on an 11 point numerical rating scale 1 month after ED visit. Secondary outcomes 1 month after ED discharge included analgesic use, functional disability, and adverse medication effects. RESULTS: Six hundred thirty-seven patients were approached for participation, 133 were eligible, and 82 were randomized. Baseline characteristics were comparable between the groups. The primary outcome, a comparison of the mean improvement in pain intensity, favored methylprednisolone by 1.3 (P = 0.10). Some secondary outcomes favored methylprednisolone, such as use of analgesic medication within the previous 24 hours (22% vs. 43%, 95% CI for difference of 20%: 0%-40%) and functional disability (19% vs. 49%, 95% CI for difference of 29%: 9%-49%). Adverse medication effects 1 week after ED discharge were reported by 32% of methylprednisolone and 24% of placebo patients (95% CI for difference of 9%: -12% to 30%). CONCLUSION: This study was a negative study, though there was a suggestion of benefit of methylprednisolone acetate in a population of young adults with acute radicular low back pain. Further work with a larger sample of patients is needed.

Randomized trial of IV dexamethasone for acute migraine in the emergency department.

BACKGROUND: It is not yet clear if corticosteroids are useful for the treatment of migraine. We determined the efficacy of 10 mg of IV dexamethasone as adjuvant therapy for patients presenting to an emergency department (ED) with acute migraine. METHODS: This was a randomized, double-blind, placebo-controlled multicenter trial. Subjects were randomized to dexamethasone 10 mg IV or placebo. As primary treatment for their migraine, all subjects received IV metoclopramide. Our primary hypotheses were the following: a greater percentage of patients with migraine who received dexamethasone would 1) achieve a headache-free state in the ED and maintain it for 24 hours and 2) have no headache-related functional impairment after ED discharge when compared to placebo. RESULTS: A total of 656 patients were approached for participation and 205 were randomized. The persistent pain-free outcome was achieved in 25% of those randomized to dexamethasone and 19% of placebo (p = 0.34). No functional impairment after ED discharge occurred in 67% of those randomized to dexamethasone and 59% of placebo (p = 0.20). In the subgroup of subjects with migraine lasting longer than 72 hours, 38% of those randomized to dexamethasone were persistently pain-free vs 13% of placebo (p = 0.06). Side effect profiles were similar, with the exception of acute medication reactions, which occurred more commonly in the dexamethasone group. CONCLUSION: A moderate dose of IV dexamethasone should not be administered routinely for the emergency department-based treatment of acute migraine, although it might be useful for patients with migraine lasting longer than 72 hours.

Development of a zona-free method of nuclear transfer in the mouse.

In the present study, a zona-free nuclear transfer (NT) technique, which had been originally developed in cattle, was modified for the mouse. Steps involved in this approach include removing the zona pellucida and enucleating without a holding pipette; sticking donor cells to the cytoplast before electric pulses are applied to fuse them and culturing reconstructed embryos individually in single droplets, to prevent aggregation. Control zona-free and zona-intact embryos from mated donors showed no significant difference in development to blastocyst, but did show reduced development to term. Removal of the zona pellucida affected the response to activation by strontium in the absence of calcium as a significant proportion of zona-free control oocytes and embryos reconstructed by NT lysed during this treatment. A comparison between cumulus and ES cells as donor cells revealed significant differences in fusion efficiency (58.1 +/- 4.0%, n = 573 vs. 42.9 +/- 2.2%, n = 2064, respectively, p < 0.001), cleavage (77.2 +/- 3.4%, n = 334 vs. 40.8 +/- 2.7%, n = 903, respectively, p < 0.001) but not for development to morula/blastocyst (8.7 +/- 2.1%, n = 334 vs. 13.9 +/- 1.8%, n = 903, respectively, p < 0.1). The stage at which embryo development arrested was also affected by donor cell type. A majority of embryos reconstructed from cumulus cells arrested at two-cell stage, usually with two nuclei, whereas those reconstructed from ES cells arrested at one-cell stage, usually with two pseudo-pronuclei. After transfer of ES cell-derived NT embryos, a viable cloned mouse was produced (3.0% of transferred embryos developed to term). These observations establish that a zona-free cloning approach is possible in the mouse, although further research is required to increase the efficiency.

A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines.

OBJECTIVE: To compare the efficacy of 20 mg of IV metoclopramide, given up to four times over 2 hours as needed for persistent headache, with 6 mg of subcutaneous sumatriptan for the emergency department treatment of migraine headaches. METHODS: This was a randomized, double-blind, clinical trial with two intervention arms. The primary endpoint was change in pain intensity as measured by an 11-point pain scale at 2 hours. Secondary endpoints included change in pain intensity at 24 hours and rates of pain-free headache relief at 2 and 24 hours. RESULTS: Two hundred two patients were screened, and 78 of 91 eligible patients were randomized. The two groups had comparable pain scores at baseline. By 2 hours, the change in pain intensity for the metoclopramide group was 7.2 compared with 6.3 for the sumatriptan group (95% CI for difference: -0.2 to 2.2). When compared at 24 hours, the metoclopramide group had improved by 6.1 compared with baseline and the sumatriptan group had improved by 5.0 (95% CI for difference: -0.6 to 2.8). At 2 hours, pain-free rates were 59% in the metoclopramide arm and 35% in the sumatriptan arm (95% CI for difference of 24%: 2 to 46%). The most common side effects at both time points were weakness, dizziness, and drowsiness, which were distributed evenly between the two groups. There were no reports of chest pain within the first 2 hours. The incidence of restlessness, stiffness, and abnormal movements was distributed equally between the two groups. CONCLUSIONS: When compared at 2 and 24 hours, aggressive (20 mg dosed up to four times) IV metoclopramide and 6 mg of subcutaneous sumatriptan relieved migraine headache pain comparably. Some secondary endpoints suggest that metoclopramide may be the preferable therapy for migraines presenting to the emergency department.

Ability of CT to alter decision making in elderly patients with acute abdominal pain.

The study objective was to assess the ability of computerized tomography (CT) to alter clinical decision-making in the evaluation of elderly Emergency Department (ED) patients with abdominal pain. A prospective, observational cohort study of a convenience sample of ED patients, 65 years of age, with abdominal or flank pain of 1-week duration was conducted. ED attending physicians completed a structured data collection instrument recording 5 primary endpoints before and after CT. Change in frequency of each of these 5 endpoints from pre- to post-CT comprised the target outcome variables. Of 104 eligible patients, CT altered the admission decision in 26% (95%CI 18, 34%)]; need for surgery in 12% (95% CI 6%, 18%); need for antibiotics in 21% (95% CI 13%, 29%) and suspected diagnosis in 45% (95% CI 35%, 55%). The proportion of cases in which physicians reported a high degree of certainty in the suspected diagnosis increased from 36% pre-CT (95%CI 26,44%) to 77% post-CT (95% CI 69, 85%). Diagnosis and disposition were altered by CT in about one-half and one-quarter of patients, respectively, concurrent with a doubling in diagnostic certainty. CT has the ability to significantly alter clinically important decisions in elderly patients with abdominal pain.

Limited usefulness of initial blood cultures in community acquired pneumonia.

OBJECTIVE: The incidence of community acquired pneumonia (CAP) is about 4 million cases per year, with a hospitalisation rate of 20%. In non-immunocompromised patients hospitalised for CAP the rate of bacteraemia is less than 7% with predictable pathogens. Despite this, guidelines still recommend use of blood cultures (BCs) to direct treatment. This study tested the primary hypothesis that the proportion of false positive BCs would exceed the proportion of true positives. A secondary aim was to quantify the frequency with which antibiotic therapy was changed based on BC results. METHOD: Consecutive adults hospitalised from an urban emergency department (ED) with CAP between January 1999 and March 2001 were assessed retrospectively for study eligibility. Those with an infiltrate consistent with pneumonia on the admission chest radiograph and at least one set of BCs taken in the ED before antibiotics were given were entered into the study. Patients hospitalised within the previous two weeks, nursing home residents, and immunosuppressed patients were excluded. RESULTS: 821 patients were admitted for CAP and 355 met inclusion criteria. The proportion of false positive BCs (10%) exceeded the proportion of true positives (9%), by 1% (95%CI -3.3% to 5.5%). Antibiotic therapy was changed on the basis of BC results in 5% of patients (95%CI 3% to 8%). CONCLUSION: The rate of false positive BCs in patients hospitalised with CAP is similar to the rate of true positives. BCs only infrequently lead to changes in antibiotic therapy, and in no instance were therapeutic changes driven by detection of resistant organisms. The results question the utility of routine BCs in immunocompetent patients with CAP.

Increased blood lead levels in severe smoke inhalation.

Lead-containing paint is common in structures built before 1977. Heated lead in burning paint can be aerosolized and absorbed directly into the bloodstream through the lungs. Acute lead intoxication has been reported in this setting. The objective of this study was to determine if victims of severe smoke inhalation secondary to closed-space fires have clinically important elevated blood lead levels. A case-control study, with a 2:1 ratio of cases to controls, was matched for age and sex. Cases were drawn from a prospective convenience sample of intubated victims of closed-space fires presenting to the ED of an urban tertiary burn center. Cases had blood lead levels obtained 24 hours postexposure. Matched control subjects had blood lead levels obtained during ED evaluation for a complaint unrelated to smoke inhalation. The difference between mean lead levels for cases and control subjects was expressed with a 95% confidence interval (CI). Among 22 cases, the mean lead level was 6.64 mug/dL (standard deviation [SD], 4.14 mug/dL). Among the 44 matched control subjects, mean lead level was 2.89 mug/dL (SD, 1.65 mug/dL). The mean difference between cases and control subjects was 3.75 mug/dL (95% confidence interval, 1.86-5.64). Although severe smoke inhalation is associated with a more than 2-fold statistically significant increase in blood lead levels, there is no evidence to suggest that these elevations are clinically important.

Reliability of the visual analog scale for measurement of acute pain.

OBJECTIVE: Reliable and valid measures of pain are needed to advance research initiatives on appropriate and effective use of analgesia in the emergency department (ED). The reliability of visual analog scale (VAS) scores has not been demonstrated in the acute setting where pain fluctuation might be greater than for chronic pain. The objective of the study was to assess the reliability of the VAS for measurement of acute pain. METHODS: This was a prospective convenience sample of adults with acute pain presenting to two EDs. Intraclass correlation coefficients (ICCs) with 95% confidence intervals (95% CIs) and a Bland-Altman analysis were used to assess reliability of paired VAS measurements obtained 1 minute apart every 30 minutes over two hours. RESULTS: The summary ICC for all paired VAS scores was 0.97 [95% CI = 0.96 to 0.98]. The Bland-Altman analysis showed that 50% of the paired measurements were within 2 mm of one another, 90% were within 9 mm, and 95% were within 16 mm. The paired measurements were more reproducible at the extremes of pain intensity than at moderate levels of pain. CONCLUSIONS: Reliability of the VAS for acute pain measurement as assessed by the ICC appears to be high. Ninety percent of the pain ratings were reproducible within 9 mm. These data suggest that the VAS is sufficiently reliable to be used to assess acute pain.

Advance directives in skilled nursing facility residents transferred to emergency departments.

OBJECTIVE: Ten years have passed since Congress enacted the Patient Self-Determination Act to promote the use of advance directives (ADs). This study was performed to determine the frequency, type, demographic distribution, and utility of ADs that accompany residents of skilled nursing facilities (SNFs) transferred to emergency departments (EDs). METHODS: This was an observational, cross-sectional cohort of SNF residents, transferred to two urban, academic EDs. Chart review and physician interviews were conducted on consecutive patients arriving during 12-hour data collection shifts. RESULTS: Among 715 patients entered, 315 [44%, 95% confidence interval (95% CI) = 40% to 48%] had an AD. Advance directives were significantly more prevalent among white (50%) than African American (34%) or Hispanic (39%) patients (p < 0.001), and varied from 0% to 94% among SNFs. Of the 315 patients with ADs, do-not-resuscitate (DNR) orders were the most prevalent (65%, 95% CI = 58% to 69%). Although 75% (95% CI = 69% to 81%) of the DNR orders addressed cardiopulmonary resuscitation (CPR), only 12% (95% CI = 8% to 16%) addressed intubation. Among 39 patients who required intubation or CPR, 44% had ADs, 82% (95% CI = 57% to 96%) of which were deemed useful. CONCLUSIONS: Despite a decade of legislation promoting their use, ADs are lacking in most SNF residents transferred to EDs for evaluation and in most settings in which a clinical indication exists for intubation or CPR. Variation in their prevalence appears to be associated with both ethnicity and SNF origin. Although about three-fourths of DNR ADs addressed CPR, only about one in ten offered guidance regarding intubation. When available, ADs are used in most instances to guide emergency care.

Randomized clinical trial of intravenous magnesium sulfate as an adjunctive medication for emergency department treatment of migraine headache.

STUDY OBJECTIVE: We test the hypothesis that intravenous magnesium sulfate is an effective adjunctive medication for treatment of acute migraine. METHODS: In this randomized, double-blind, placebo-controlled trial, adults presenting to 2 urban emergency departments with headache meeting International Headache Society criteria for acute migraine received either 20 mg of intravenous metoclopramide plus 2 g of intravenous magnesium sulfate or 20 mg of intravenous metoclopramide plus a placebo of intravenous saline solution at 15-minute intervals for a maximum of 3 doses or until pain relief occurred. At 0, 15, 30, and 45 minutes, patients recorded pain intensity using a standard visual analog scale (VAS). The primary study end point was the between-group difference in pain improvement when initial and final VAS scores were compared. RESULTS: Of 44 patients enrolled (21 randomized to metoclopramide plus magnesium and 23 to metoclopramide plus placebo), 42 (95%) were women. Baseline features were comparable in both groups. Each group experienced a more than 50-mm improvement in VAS score during the study. However, this improvement was smaller in the magnesium group for the primary end point (16-mm difference favoring placebo [95% confidence interval (CI) -2 to 34 mm]), as was the proportion with normal functional status at their final rating (36% absolute difference also favoring placebo [95% CI 7% to 65%]). Using a 50% reduction in pain to dichotomize VAS scores, the number needed to harm with magnesium plus metoclopramide versus metoclopramide alone is 4 patients (95% CI 2 to 36). CONCLUSION: Although this result was unexpected, our data suggest that the addition of magnesium to metoclopramide may attenuate the effectiveness of metoclopramide in relieving migraine. Countertherapeutic cerebral vasodilatation caused by magnesium is a plausible, although unproven, explanation for this finding. Because of the preponderance of women in our trial, these data may not be generalizable to men.

Prospective validation of clinically important changes in pain severity measured on a visual analog scale.

BACKGROUND: In a landmark hypothesis-generating study, Todd et al found that a difference of approximately 13 mm (95% confidence interval [CI] 10 to 17 mm) on a visual analog scale (VAS) represented the minimum change in acute pain that was clinically significant in a cohort of trauma patients. STUDY OBJECTIVE: We test the hypothesis that the minimum clinically significant change in pain as measured by the VAS in an independent, more heterogeneous validation cohort is approximately 13 mm. METHODS: This was a prospective, observational cohort study of adults presenting to 2 urban emergency departments with pain. At 30-minute intervals during a 2-hour period, patients marked a VAS and were asked if their pain was "much less," "a little less," "about the same," "a little more," or "much more." All data were obtained without reference to prior VAS scores. The minimum clinically significant change in pain was defined a priori as the difference in millimeters between the current and immediately preceding VAS scores when "a little more" or "a little less pain" was reported. RESULTS: Ninety-six patients enrolled in the study, providing 332 paired pain measurements. There were 141 paired measurements designated by patients as "a little less" or "a little more" pain. The mean clinically significant difference between consecutive ratings of pain in the combined "little less" or "little more" groups was 13 mm (95% CI 10 to 16 mm). The difference between this finding and that of Todd et al was 0 mm (95% CI -4 to 4 mm). CONCLUSION: These data are virtually identical to previous findings indicating that a difference of 13 mm on a VAS represents, on average, the minimum change in acute pain that is clinically significant.

Effect of age on acute pain perception of a standardized stimulus in the emergency department.

STUDY OBJECTIVE: The study was undertaken to determine whether pain perception is different in elderly patients than in younger patients. METHODS: A cross-sectional, observational study was conducted at 2 urban academic emergency departments. Adult patients (> or =18 years of age) who required an 18-gauge intravenous catheter as part of their ED care were eligible. Patients were excluded for the following conditions: more than one attempt at intravenous catheter placement, altered mental status, visual impairment, intoxication, distracting pain, or abnormal upper extremities. Patients were asked to indicate on a 10-cm visual analog scale (VAS) the amount of pain they had at baseline immediately before intravenous catheter placement. They were then asked to indicate on a separate VAS the amount of pain caused by intravenous catheter placement. Patients aged 65 years and older were defined a priori as elderly. RESULTS: Of 100 patients enrolled in the study, 32 (32%) were elderly. Elderly patients reported significantly less pain than nonelderly patients (Delta = -15 mm, 95% confidence interval -26 to -4 mm). Pain of intravenous catheter placement was not associated with sex, baseline pain, site of intravenous catheter insertion, or level of training of the individual placing the intravenous catheter. CONCLUSION: Elderly patients experienced less acute pain than their younger counterparts in response to a standardized stimulus in a clinical setting. This difference is both statistically and clinically significant. This may have clinical implications for the assessment and treatment of acute pain in the elderly.