Methotrexate has been used in treatment of rheumatoid arthritis (RA) since the 1980s and to this day is often the first line medication for RA treatment. In this review, we examine multiple ...hypotheses to explain the mechanism of methotrexate efficacy in RA. These include folate antagonism, adenosine signaling, generation of reactive oxygen species (ROS), decrease in adhesion molecules, alteration of cytokine profiles, and polyamine inhibition amongst some others. Currently, adenosine signaling is probably the most widely accepted explanation for the methotrexate mechanism in RA given that methotrexate increases adenosine levels and on engagement of adenosine with its extracellular receptors an intracellular cascade is activated promoting an overall anti-inflammatory state. In addition to these hypotheses, we examine the mechanism of methotrexate in RA from the perspective of its adverse effects and consider some of the newer genetic markers of methotrexate efficacy and toxicity in RA. Lastly, we briefly discuss the mechanism of additive methotrexate in the setting of TNF-α inhibitor treatment of RA. Ultimately, finding a clear explanation for the pathway and mechanism leading to methotrexate efficacy in RA, there may be a way to formulate more potent therapies with fewer side effects.
Objective
We conducted a randomized trial among emergency department patients with migraine to determine the relative impact on migraine‐associated symptoms of hydromorphone, an opioid, versus ...prochlorperazine, an antidopaminergic antiemetic.
Methods
This was a post hoc analysis of data from a double‐blind study registered at http://clinicaltrials.gov (NCT02389829). Patients who met International Classification of Headache Disorders, 3rd edition criteria for migraine without aura or for probable migraine without aura were eligible for participation. Participants received either hydromorphone 1 mg IV or prochlorperazine 10 mg IV plus diphenhydramine 25 mg IV and could receive a second dose of the same medication 1 h later if needed. The outcomes were sustained relief of nausea, photophobia, and phonophobia.
Results
A total of 127 patients were enrolled, of whom 63 received prochlorperazine and 64 received hydromorphone. Of 49 patients in the prochlorperazine arm who reported nausea at baseline, 34 (69.4%) reported complete resolution without relapse versus 15/49 (30.6%) in the hydromorphone arm (absolute risk reduction ARR = 38.8%, 95% CI: 20.5%–57.0%, p < 0.001). Of 55 patients in the prochlorperazine arm who reported photophobia at baseline, 23 (41.8%) reported complete resolution without relapse versus 13/62 (20.9%) patients treated with hydromorphone (ARR = 20.8%, 95% CI: 4.3%–37.3%, p = 0.014). Of 56 patients in the prochlorperazine arm who reported phonophobia at baseline, 25 (44.6%) reported complete resolution without relapse versus 16/59 (27.1%) in the hydromorphone arm (ARR = 17.5%, 95% CI: 0.3%–34.8%, p = 0.049). For adverse events, three patients in the prochlorperazine arm reported anxiety or restlessness, and nine patients in the hydromorphone arm reported dizziness or weakness.
Conclusions
Prochlorperazine plus diphenhydramine is more efficacious than hydromorphone for the treatment of migraine‐associated symptoms.
The fact that actual economic advance over time normally means producing and consuming different things is usually left implicit in modern models of economic growth. By contrast, qualitative ...change--new goods and services, and better versions of what already existed--is central to Robert Gordon's history of the improvement of American living standards since 1870. A major contribution of his fine-grained account of this experience is to make clear what this improvement has meant, and why it has mattered to ordinary citizens.
Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are useful for a variety of musculoskeletal injuries. It is not known whether topical NSAIDs should be used for patients presenting with acute ...nonradicular musculoskeletal low back pain.
We conducted a randomized, placebo-controlled double-blind study in which patients 18 to 69 years of age visiting the emergency department (ED) with acute, nontraumatic, nonradicular, musculoskeletal low back pain were randomized at the time of discharge to treatment with 400 mg oral ibuprofen + placebo topical gel, 1% diclofenac topical gel + oral placebo, or 400 mg ibuprofen + 1% diclofenac topical gel. We measured outcomes using the Roland Morris Disability Questionnaire (RMDQ), a 24-item yes/no instrument about the effect of back pain on a respondent’s daily activities. The primary outcome was change in RMDQ score between ED discharge and 2 days later. Medication-related adverse events were elicited by asking whether the study medications caused any new symptoms.
In total, 3,281 patients were screened for participation, and 198 were randomized. Overall, 36% of the population were women, the mean age was 40 years (standard deviation, 13), and the median RMDQ score at baseline was 18 (25th to 75th percentile: 13 to 22), indicating substantial low back-related functional impairment. In total, 183 (92%) participants provided primary outcome data. Two days after the ED visit, the ibuprofen + placebo group had improved by 10.1 (95% confidence interval CI 7.5 to 12.7), the diclofenac gel + placebo group by 6.4 (95% CI 4.0 to 8.8), and the ibuprofen + diclofenac gel by 8.7 (95% CI 6.3 to 11.1). The between-group differences were as follows: ibuprofen versus diclofenac, 3.7 (95% CI 0.2 to 7.2); ibuprofen versus both medications 1.4 (95% CI −2.1 to 4.9); and diclofenac versus both medications, 2.3 (95% CI −5.7 to 1.0). Medication-related adverse events were reported by 3/60 (5%) ibuprofen patients, 1/63 (2%) diclofenac patients, and 4/64 (6%) patients who received both.
Among patients with nontraumatic, nonradicular acute musculoskeletal low back pain discharged from an ED, topical diclofenac was probably less efficacious than oral ibuprofen. It demonstrated no additive benefit when coadministered with oral ibuprofen.
Diagnostic testing is of limited value among patients with migraine who present to an emergency department. Various nonopioid, disease-specific treatments are available for patients who present to an ...emergency department with migraine headache and associated features. Emergency physicians should recognize that the acute migraine presentation is part of an underlying disorder; care should be geared to the underlying headache disorder in addition to the acute attack.
To determine the prevalence of and risk factors associated with opioid use in the treatment of migraine, we examined demographics and clinical characteristics of 867 individuals who reported using ...opioids for the treatment of migraine.
We analyzed data from the CaMEO study (Chronic Migraine Epidemiology and Outcomes), a cross-sectional, longitudinal, Internet study, to compare sociodemographics, clinical characteristics, and migraine burden/disability of opioid users vs nonusers. Covariates were entered as categorical or continuous variables. Factors associated with opioid use were identified using nested, multivariable binary logistic regression models.
Of 2,388 respondents with migraine using prescription medications for acute treatment, 36.3% reported that they currently used or kept on hand opioid medications to treat headaches. Current opioid users had significantly more comorbidities, greater headache-related burden, and poorer quality of life than nonusers. Regression models revealed factors significantly associated with opioid use, including male sex, body mass index, allodynia, increasing monthly headache frequency, Total Pain Index score (excluding head, face, neck/shoulder), anxiety, depression, ≥1 cardiovascular comorbidity, and emergency department/urgent care use for headache in the past 6 months. Self-reported physician-diagnosed migraine/chronic migraine was associated with significantly decreased likelihood of opioid use.
Of respondents who were using acute prescription medications for migraine, more than one-third used or kept opioids on hand, contrary to guidance. This analysis could not distinguish risk factors from consequences of opioid use; thus further research is needed to guide the development of strategies for reducing the inappropriate use of opioids in migraine.
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