Monthly Archives: August 2015

Nonsteroidal anti-inflammatory drugs and non-opioids for acute renal colic.

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Afshar K1, Jafari S, Marks AJ, Eftekhari A, MacNeily AECochrane Database Syst Rev. 2015 Jun 29;6:CD006027. doi: 10.1002/14651858.CD006027.pub2.



Renal colic is acute pain caused by urinary stones. The prevalence of urinary stones is between 10% and 15% in the United States, making renal colic one of the common reasons for urgent urological care. The pain is usually severe and the first step in the management is adequate analgesia. Many different classes of medications have been used in this regard including non-steroidal anti-inflammatory drugs and narcotics.


The aim of this review was to assess benefits and harms of different NSAIDs and non-opioids in the treatment of adult patients with acute renal colic and if possible to determine which medication (or class of medications) are more appropriate for this purpose. Clinically relevant outcomes such as efficacy of pain relief, time to pain relief, recurrence of pain, need for rescue medication and side effects were explored.


We searched the Cochrane Renal Group’s Specialised Register (to 27 November 2014) through contact with the Trials’ Search Co-ordinator using search terms relevant to this review.


Only randomised or quasi randomised studies were included. Other inclusion criteria included adult patients with a clinical diagnosis of renal colic due to urolithiasis, at least one treatment arm included a non-narcotic analgesic compared to placebo or another non-narcotic drug, and reporting of pain outcome or medication adverse effect. Patient-rated pain by a validated tool, time to relief, need for rescue medication and pain recurrence constituted the outcomes of interest. Any adverse effects (minor or major) reported in the studies were included.


Abstracts were reviewed by at least two authors independently. Papers meeting the inclusion criteria were fully reviewed and relevant data were recorded in a standardized Cochrane Renal Group data collection form. For dichotomous outcomes relative risks and 95% confidence intervals were calculated. For continuous outcomes the weighted mean difference was estimated. Both fixed and random models were used for meta-analysis. We assessed the analgesic effects using four different outcome variables: patient-reported pain relief using a visual analogue scale (VAS); proportion of patients with at least 50% reduction in pain; need for rescue medication; and pain recurrence. Heterogeneity was assessed using the I² test.


A total of 50 studies (5734 participants) were included in this review and 37 studies (4483 participants) contributed to our meta-analyses. Selection bias was low in 34% of the studies or unclear in 66%; performance bias was low in 74%, high in 14% and unclear in 12%; attrition bias was low in 82% and high in 18%; selective reporting bias low in 92% of the studies; and other biases (industry funding) was high in 4%, unclear in 18% and low in 78%.Patient-reported pain (VAS) results varied widely with high heterogeneity observed. For those comparisons which could be pooled we observed the following: NSAIDs significantly reduced pain compared to antispasmodics (5 studies, 303 participants: MD -12.97, 95% CI -21.80 to – 4.14; I² = 74%) and combination therapy of NSAIDs plus antispasmodics was significantly more effective in pain control than NSAID alone (2 studies, 310 participants: MD -1.99, 95% CI -2.58 to -1.40; I² = 0%).NSAIDs were significantly more effective than placebo in reducing pain by 50% within the first hour (3 studies, 197 participants: RR 2.28, 95% CI 1.47 to 3.51; I² = 15%). Indomethacin was found to be less effective than other NSAIDs (4 studies, 412 participants: RR 1.27, 95% CI 1.01 to 1.60; I² = 55%). NSAIDs were significantly more effective than hyoscine in pain reduction (5 comparisons, 196 participants: RR 2.44, 95% CI 1.61 to 3.70; I² = 28%). The combination of NSAIDs and antispasmodics was not superior to NSAIDs only (9 comparisons, 906 participants: RR 1.00, 95% CI 0.89 to 1.13; I² = 59%). The results were mixed when NSAIDs were compared to other non-opioid medications.When the need for rescue medication was evaluated, Patients receiving NSAIDs were significantly less likely to require rescue medicine than those receiving placebo (4 comparisons, 180 participants: RR 0.35, 95% CI 0.20 to 0.60; I² = 24%) and NSAIDs were more effective than antispasmodics (4 studies, 299 participants: RR 0.34, 95% CI 0.14 to 0.84; I² = 65%). Combination of NSAIDs and antispasmodics was not superior to NSAIDs (7 comparisons, 589 participants: RR 0.99, 95% CI 0.62 to 1.57; I² = 10%). Indomethacin was less effective than other NSAIDs (4 studies, 517 participants: RR 1.36, 95% CI 0.96 to 1.94; I² = 14%) except for lysine acetyl salicylate (RR 0.15, 95% CI 0.04 to 0.65).Pain recurrence was reported by only three studies which could not be pooled: a higher proportion of patients treated with 75 mg diclofenac (IM) showed pain recurrence in the first 24 hours of follow-up compared to those treated with 40 mg piroxicam (IM) (60 participants: RR 0.05, 95% CI 0.00 to 0.81); no significant difference in pain recurrence at 72 hours was observed between piroxicam plus phloroglucinol and piroxicam plus placebo groups (253 participants: RR 2.52, 95% CI 0.15 to12.75); and there was no significant difference in pain recurrence within 72 hours of discharge between IM piroxicam and IV paracetamol (82 participants: RR 1.00, 95% CI 0.65 to 1.54).Side effects were presented inconsistently, but no major events were reported.


Although due to variability in studies (inclusion criteria, outcome variables and interventions) and the evidence is not of highest quality, we still believe that NSAIDs are an effective treatment for renal colic when compared to placebo or antispasmodics. The addition of antispasmodics to NSAIDS does not result in better pain control. Data on other types of non-opioid, non-NSAID medication was scarce.Major adverse effects are not reported in the literature for the use of NSAIDs for treatment of renal colic.

Treating neuropathic pain with amitriptyline


Moore RA, Derry S, Aldington D, et al. Amitriptyline for neuropathic pain in adults. Cochrane Database Syst Rev. 2015 Jul 6;7:CD008242. (Review) PMID: 26146793

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 12, 2012. That review considered both fibromyalgia and neuropathic pain, but the effects of amitriptyline for fibromyalgia are now dealt with in a separate review.Amitriptyline is a tricyclic antidepressant that is widely used to treat chronic neuropathic pain (pain due to nerve damage). It is recommended as a first line treatment in many guidelines. Neuropathic pain can be treated with antidepressant drugs in doses below those at which the drugs act as antidepressants.

OBJECTIVES: To assess the analgesic efficacy of amitriptyline for relief of chronic neuropathic pain, and the adverse events associated with its use in clinical trials. SEARCH

METHODS: We searched CENTRAL, MEDLINE, and EMBASE to March 2015, together with two clinical trial registries, and the reference lists of retrieved papers, previous systematic reviews, and other reviews; we also used our own hand searched database for older studies.
SELECTION CRITERIA: We included randomised, double-blind studies of at least four weeks` duration comparing amitriptyline with placebo or another active treatment in chronic neuropathic pain conditions.
DATA COLLECTION AND ANALYSIS: We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks` duration, parallel design), second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison, and third tier from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both.

MAIN RESULTS: We included 15 studies from the earlier review and two new studies (17 studies, 1342 participants) in seven neuropathic pain conditions. Eight cross-over studies with 302 participants had a median of 36 participants, and nine parallel group studies with 1040 participants had a median of 84 participants. Study quality was modest, though most studies were at high risk of bias due to small size.There was no first-tier or second-tier evidence for amitriptyline in treating any neuropathic pain condition. Only third-tier evidence was available. For only two of seven studies reporting useful efficacy data was amitriptyline significantly better than placebo (very low quality evidence).More participants experienced at least one adverse event; 55% of participants taking amitriptyline and 36% taking placebo. The risk ratio (RR) was 1.5 (95% confidence interval (CI) 1.3 to 1.8) and the number needed to treat for an additional harmful outcome was 5.2 (3.6 to 9.1) (low quality evidence). Serious adverse events were rare. Adverse event and all-cause withdrawals were not different, but were rarely reported (very low quality evidence).

AUTHORS’ CONCLUSIONS: Amitriptyline has been a first-line treatment for neuropathic pain for many years. The fact that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has to be balanced against decades of successful treatment in many people with neuropathic pain. There is no good evidence of a lack of effect; rather our concern should be of overestimation of treatment effect. Amitriptyline should continue to be used as part of the treatment of neuropathic pain, but only a minority of people will achieve satisfactory pain relief. Limited information suggests that failure with one antidepressant does not mean failure with all.

Medical marijuana: Show me the data


Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA. 2015 Jun 23-30;313(24):2456-73. doi: 10.1001/jama.2015.6358. (Review) PMID: 26103030

IMPORTANCE: Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear.

OBJECTIVE: To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids.

DATA SOURCES: Twenty-eight databases from inception to April 2015.

STUDY SELECTION: Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome.

DATA EXTRACTION AND SYNTHESIS: Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis. MAIN OUTCOMES AND

MEASURES: Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs.

RESULTS: A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], -0.46 [95% CI, -0.80 to -0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, -0.36 [95% CI, -0.69 to -0.05]; 7 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.

CONCLUSIONS AND RELEVANCE: There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.

Very Early Mobilization of All Patients with Acute Stroke May Not Improve 3-Month Outcomes

Reference: AAVERT trial (Lancet 2015 July 4;386(9988):46) (level 2 [mid-level] evidence)

Early mobilization (sitting out-of-bed, standing, and walking) is recommended for less severely affected patients after acute stroke to reduce the risk of complications such as pneumonia, deep vein thrombosis, pulmonary embolism, and pressure ulcers (Stroke 2013 Mar;44(3):870). The optimal timing and frequency of early mobilization, however, has not been well-defined. One small randomized trial suggested that mobilization within 52 hours may reduce the risk of life-threatening complications compared to mobilization after 7 days, but the overall complication rate was not significantly different between groups (Clin Rehabil 2012 May;26(5):451). Results of trials examining mobilization within 24 hours have been conflicting. A meta-analysis of 2 small trials found very early mobilization decreased complications and improved independence (Stroke 2010 Nov;41(11):2632), while one small trial published since suggested mobilization within 24 hours might be associated with increased mortality and poorer global function (Stroke 2012 Sep;43(9):2389). To resolve the uncertainty about the impact of early mobilization, a recent randomized trial compared very early mobilization vs. routine mobilization as part of care in the stroke unit in 2,104 adults (mean age 73 years and 61% male) with ischemic or hemorrhagic stroke admitted to the stroke unit within 24 hours of symptom onset.

Very early mobilization began within 24 hours of stroke onset and included at least 3 out-of-bed sessions focusing on sitting, standing, or walking. Usual care varied by treatment location, but thrombolysis with tissue plasminogen activator (tPA) was allowed. Overall, mobilization within 24 hours occurred in 92% of patients randomized to very early mobilization compared to 59% of patients randomized to usual care with a median time to first mobilization of 18.5 hours vs. 22.4 hours, respectively (p < 0.0001). At 3 months post-stroke, 46% of patients with early mobilization and 50% of patients with usual care had a favorable outcome, defined as a modified Rankin Scale score of 0-2 (p = 0.004, NNH 25). These results were consistent, though often not significant, in prespecified subgroup analyses by age, stroke severity, stroke type, recombinant tPA use, and region of recruitment. There were no significant differences in the distribution of patients across all 0-6 point modified Rankin Scale scores, however. There were also no significant differences between groups in mortality, time to walking unassisted, and adverse events.

While previous trials evaluating early mobilization after acute stroke were limited by the small numbers of patients included, the current trial is well powered to detect small differences in patient outcomes after acute stroke. Indeed, it is more than 10 times the size of all previous mobilization trials combined. One drawback of the present trial, however, was that the median time to first mobilization was less than 24 hours in both randomized groups. This reflects the fact that the trials included patients with both mild strokes and severe strokes, in fact approximately 40% of patients in both groups were able to walk independently at baseline. Nonetheless, the very early mobilization group had their median time to first mobilization approximately 4 hours before the usual care group and there was an absolute difference of 33% in the rate of patients being mobilized within 24 hours. These differences in mobilization did not benefit the earlier mobilization group, and very early mobilization may have even negatively impacted global functioning at 3 months. Finally, unlike in previous trials, this trial found that early mobilization did not decrease adverse events, including immobilization-related serious adverse events. Overall, the results of this trial suggest that benefits previously associated with early mobilization do not require mobilization to begin within 24 hours. This suggests current recommendations may need to be updated.

For more information see the Stroke (acute management) topic in DynaMed.