Monthly Archives: March 2016

Cannabidiol May Reduce Seizures in Children and Young Adults with Treatment-Resistant Epilepsy

Reference – Lancet Neurol 2015 Dec 23 early online (level 3 [lacking direct] evidence)

  • Anecdotal reports suggest medical marijuana or marijuana-derived compounds might benefit patients with intractable epilepsy, though evidence from clinical studies supporting this claim is extremely limited.
  • A recent uncontrolled trial including 214 children and young adults with treatment-resistant, intractable epilepsy reported a median 36.5% reduction in motor seizures and 34.6% reduction in total seizures after 12 weeks of cannabidiol treatment.
  • Cannabidiol was well tolerated, with most patients reporting only mild-to-moderate, transient adverse events including somnolence, decreased appetite, diarrhea, fatigue, and convulsion.

Up to one third of patients with epilepsy are resistant to medical therapy and are at an increased risk of injury, poor quality of life, and premature death (Lancet 2015 Mar 7;385(9971):884, N Engl J Med 2011 Sep 8;365(10):919).  Anecdotal evidence suggests cannabidiol, 1 of the 2 main cannabinoids found in marijuana, might reduce seizures in drug-resistant patients (Epilepsy Behav 2013 Dec;29(3):574, Lancet 2015 Oct 24;386(10004):1615).  This limited evidence has generated great interest in the potential use of this compound as an add-on therapy to antiepileptic drugs, particularly in rare pediatric epilepsies such as Dravet syndrome, Lennox-Gastaut syndrome, and Doose syndrome.  In response, many states have approved medical marijuana (or cannabidiol extracts) specifically for children and adults with intractable epilepsy.  However, the efficacy and safety of using cannabinoids for treating patients with epilepsy, especially children, remains unknown.  To further examine this issue, a recent study evaluated oral cannabidiol in 214 children and young adults aged 1-30 years (mean age 11 years) with treatment-resistant, intractable, childhood onset epilepsy.  All patients had ≥ 4 countable seizures with a motor component in a 4-week period and were receiving stable treatment for at least 4 weeks before enrollment.  Cannabidiol dosing began at 2-5 mg/kg/day and was titrated up weekly until it was no longer tolerated or the maximum dose (25 mg/kg/day or 50 mg/kg/day depending on study site) was achieved.

Only 64% of patients were assessed in the efficacy analysis, which included patients with ≥ 12 weeks follow-up, but excluded patients who had no motor seizures during a 4-week pretreatment baseline period.  The most common epilepsy syndromes in this group were Dravet syndrome (23%) and Lennox-Gastaut syndrome (22%).  The mean cannabidiol dose was 22.7 mg/kg at 12 weeks and 30% of patients were eventually titrated to the maximum 50 mg/kg daily dose.  At the 12-week follow-up, the median number of monthly motor seizures had decreased from 30 at baseline to 15.8, with a median 36.5% decrease in monthly motor seizures.  During weeks 8-12 of treatment, 11% of patients were free from motor seizures and 7% were free from all seizures.  Efficacy of cannabidiol appears to be influenced by seizure type, with the greatest reduction seen in patients with focal seizures (55% reduction) or atonic seizures (54.3% reduction).  Overall, cannabidiol reduced total seizures by 34.6%.

Twenty-five additional patients (12%), most of whom had been excluded for lack of motor seizures during the baseline period, were included in the safety analysis.  Adverse events were reported in 79% of patients, though most were mild-to-moderate and transient.  The most commonly reported adverse events were somnolence, decreased appetite, diarrhea, fatigue, and convulsion.  Only 12% of patients reported serious adverse events that were possibly related to treatment, most frequently status epilepticus.

The results of this study are promising, showing a large reduction in seizures in children and young adults with treatment-resistant epilepsy with minimal adverse effects.  With 137 patients included in the efficacy analysis and 162 patients included in the safety analysis, this is the largest study to date on the effects of cannabidiol in this population.  Even though this drug is not yet available, this study still informs the discussion about the potential benefit of marijuana in this group of patients.  There are a number of potential sources of bias to consider, however.  There was no control group to truly determine efficacy or assess the potential for a placebo effect.  This is especially important in epilepsy where there is a natural variation in seizure frequency.  In addition, the 12-week follow-up period only allows for the assessment of immediate treatment effect, but long-term efficacy and safety remain unknown.  Finally, 24% of patients were excluded from all analyses because they did not have 12 weeks of follow-up.  Overall, the results of this study suggest that cannabidiol may help reduce seizures for severe, drug-resistant epilepsy, but randomized controlled trials are clearly needed.

For more information, see the Medical uses of cannabinoids and Epilepsy in children topics in DynaMed Plus. DynaMed users click here and here.

Antibiotics in Women with Uncomplicated Urinary Tract Infections May Not Be Necessary

Reference – BMJ 2015 Dec 23;351:h6544 (level 1 [likely reliable] evidence)

  • Immediate antibiotic therapy is currently recommended for women with uncomplicated urinary tract infections (UTI), although a portion of these infections may be self-limited.
  • In women not immediately treated with antibiotics, 65% had symptom resolution with ibuprofen alone and 35% required antibiotic treatment.
  • The time to symptom resolution was significantly longer with ibuprofen.

Increasing rates of antibiotic resistance have strengthened the need for judicious antibiotic use and antimicrobial stewardship.  Current recommendations support immediate antibiotic therapy for uncomplicated urinary tract infections (UTIs) (Clin Infect Dis 2011 Mar 1;52(5):e103, EAU 2015 Mar PDF), even though some data suggests that many uncomplicated UTIs are self-limited (Curr Infect Dis Rep 2013 Apr;15(2):124).  To assess the potential to treat UTI symptoms without antibiotics, a recent randomized trial compared ibuprofen 400 mg 3 times daily vs. single dose fosfomycin 3 g in 494 women aged 18-65 years with symptoms of uncomplicated UTI.  UTI symptoms considered for trial inclusion were dysuria or frequency/urgency of micturition, with or without lower abdominal pain.  Women were excluded for symptoms of upper urinary tract infection including fever or loin tenderness.  Both groups received placebo pills for the corresponding active treatment given to the other group to maintain blinding. Urine cultures and dipstick tests were performed, but the results did not inform eligibility.  All women were advised to consult their general practitioner if symptoms persisted or worsened, at which point antibiotic treatment was prescribed at the discretion of the practitioner based on the initial urine culture results.

Ten women were incorrectly screened and excluded from the trial after randomization.  Among the 484 women included in the intention-to-treat analysis, 92% (446 women) completed the 28 day follow-up.  Urine culture results were available for 471 women, with a positive urine culture (> 100 colony forming units/mL) in 76% (360 women).  Comparing ibuprofen vs. fosfomycin at day 28, antibiotics were prescribed to 35% vs. 100% (p < 0.001).  The total number of antibiotic courses prescribed within 28 days was 94 in the 222 women treated with ibuprofen vs. 283 in the 224 women treated with fosfomycin (p < 0.001).  This corresponds to an overall 66.5% incidence rate reduction in antibiotic use in the ibuprofen group.  In a subgroup analysis of women with a positive urine culture, ibuprofen was associated with a 58.5% reduction in antibiotic use.  However, ibuprofen was associated with an increased time to symptom resolution.  Only 39% of women treated with ibuprofen had symptom resolution at day 4 compared to 56% treated with fosfomycin (p < 0.001).  At day 7, symptom resolution occurred in 70% with ibuprofen vs. 82% with fosfomycin (p = 0.004).  Although there was no significant difference in symptom worsening within 7 days, there was a nonsignificant increase in the rate of pyelonephritis in the ibuprofen group (5 cases vs. 1 case).

In this trial, 65% of women with an uncomplicated UTI initially treated with ibuprofen recovered without antibiotic treatment.  While treatment with ibuprofen was associated with an increased total symptom burden within the first 7 days, the mean duration of symptoms was only 1 day longer with ibuprofen compared to fosfomycin.  The number of pyelonephritis cases was higher in women receiving ibuprofen, but the overall rate was low and the difference did not reach statistical significance. This potential for reducing antibiotic use is analogous to the current treatment of otitis media. For many children with nonsevere otitis media, the recommended approach is shared decision making with the parents regarding the choice between antibiotics or observation with close follow-up.  The results of this trial suggest that for women with mild uncomplicated UTIs, it may be reasonable to counsel about the potential for infection resolution without antibiotics and give the option to forgo antibiotics unless symptoms persist or worsen. One option is to empower the patient by giving a prescription that can be filled at the patient’s discretion, which has been shown to reduce the use of antibiotics in patients presenting with respiratory tract infections.

For more information, please see the Uncomplicated urinary tract infection (UTI) (pyelonephritis and cystitis) topic in DynaMed Plus.