OBJECTIVES To conduct a systematic review and analysis of trial data submitted to the US Food and Drug Administration (FDA) to identify possible causes for the failure of pediatric trials of triptans for treatment of migraines. DATA SOURCE The FDA website for drug information and published literature. STUDY SELECTION All pediatric efficacy and pharmacokinetics trial data of drugs used for abortive treatment of migraine submitted to the FDA from January 1, 1999, through December 31, 2011. MAIN OUTCOME MEASURES Patient demographic baseline characteristics, inclusion and exclusion criteria, trial designs, efficacy end points, and pharmacokinetic profiles were analyzed and compared across drug products. RESULTS We analyzed data for sumatriptan succinate nasal spray and zolmitriptan, eletriptan hydrobromide, almotriptan malate, and rizatriptan benzoate tablets. Seven efficacy trials had a randomized, double-blinded, placebo-controlled, parallel-group trial design. In 4 trials, patients were required to have a history of migraine attacks lasting at least 4 hours. High response rates for placebo were observed in all trials, with pain relief at 2 hours ranging from 53% to 57.5%. Nonrandomization of patients with an early placebo response design was used in the rizatriptan trial in 2011. Compared with the rizatriptan trial conducted in 1999, the 2011 rizatriptan trial reduced the placebo response rate by 6% for headache freedom at the 2-hour posttreatment end point owing to study design. The pharmacokinetic profiles between adolescents and adults were statistically similar. CONCLUSIONS High placebo response rates are consistent across all trials and may represent the principal challenge in pediatric trials of drugs for abortive treatment of migraine. Enrichment with selection of subjects with long-lasting migraine attacks is not sufficient to overcome high placebo response rates. Another enrichment strategy, the nonrandomization of patients with an early placebo response, successfully reduces the high placebo response rate for rizatriptan and is a trial design that should be considered for future pediatric trials of abortive migraine therapeutics.
"Placebo research, defined as the investigation of the mechanisms underlying suggestive and conditioned healing processes , has been mostly done in adults, and it remains unclear how and to what extent children form placebo effects  . On the one hand, there is evidence from clinical studies that placebo responses are present in a variety of pediatric conditions including attention-deficit/hyperactivity disorder , asthma , atopic dermatitis , seasonal allergic conjunctivitis , autism , depression , epilepsy , functional gastrointestinal conditions , chronic fatigue syndrome , hypertension , migraine , and syncope . On the other hand, it is important to understand whether the placebo mechanisms that have been explored so far are uniquely important for adults as opposed to children. "
[Show abstract][Hide abstract] ABSTRACT: Pain modulation by placebo mechanisms is one of the most robust and best-studied phenomena, yet almost all research investigating the mechanisms and implications of the placebo analgesia are based on adult research. After highlighting crucial aspects that need to be considered in studying pain modulation in children, this comprehensive review examines studies related to pain modulation with an emphasis on factors such as age, neural development and pain measures. Psychological mechanisms underlying placebo effects including: 1) verbally-induced expectations; 2) conditioning and learning mechanisms; 3) child-parent-physician interactions are critically discussed. Taken together, research suggests that placebo mechanisms can impact therapeutic outcomes and potentially be exploited clinically to improve clinical outcomes in pediatric population. Recommendations for further investigating the mechanistic bases and harnessing placebo effects for supportive therapeutic applications are given.
[Show abstract][Hide abstract] ABSTRACT: Objective:
the goal of this prospective and double-blind study was to compare the efficacy of amitriptyline and topiramate for the prevention of pediatric chronic daily headache (CDH).
Research design and methods:
fifty-seven children (aged 9-16 yr) diagnosed with CDH were randomly assigned to two groups: group A (n = 29 patients) received amitriptyline 0.5 mg/kg/d and group B (n = 28 patients) received topiramate 25 mg/d increasing up to 100 mg/d according to patient response. Treatment response was monitored for at least 4 months.
fifty-five percent of the patients in group A responded to amitriptyline and 61% of patients in group B responded to topiramate as defined by a reduction of more than 50% in monthly headache frequency. There was no significant difference in responder rate or adverse event rate between the two groups (p > 0.05). By the end of the 4-month treatment period, there were no significant differences in the final average severity and monthly frequency of headaches between treatment groups.
these results suggest that the efficacy and tolerability of topiramate is equivalent to that of amitriptyline for reducing the frequency of headache in pediatric CHD patients.
The International journal of neuroscience 02/2013; 123(8). DOI:10.3109/00207454.2013.776048 · 1.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To review the pharmacokinetics, efficacy, tolerability, and patient acceptance of zolmitriptan nasal spray (NS).
Gastroparesis may delay or diminish the absorption of oral triptans, and nausea or vomiting may do the same and/or make it difficult to take a tablet. Some migraineurs require or prefer faster relief than oral medications provide. Injectable triptans provide the fastest drug delivery into the bloodstream, but many patients are reluctant to use them. Nasal sprays may address some of the problems with tablets and injectables while still providing rapid absorption of drug.
Significant levels of zolmitriptan NS are detectable in plasma within 2-5 minutes, and the rapid absorption is due to early uptake through the nasal mucosa. In 2 randomized trials, users of zolmitriptan NS were significantly more likely than placebo recipients to be pain-free at 15 minutes post-dose, the first time point measured, and about half of patients had sustained response at 24 hours. Studies in which patients could treat a migraine of any severity have documented significant headache response or relief with zolmitriptan NS at 10 minutes. In one trial, the rate of total symptom relief was significantly better with the NS than with placebo from 30 minutes post-dose. The most common side effect of zolmitriptan NS is unusual taste. Patient satisfaction studies indicate that zolmitriptan NS is appreciated for its speed of onset, ease of use, reliability, and overall efficacy.
Zolmitriptan NS provides onset of headache relief within 10 minutes for some patients and quickly abolishes some of the major migraine symptoms. Good candidates are migraineurs whose episodes rapidly escalate to moderate-to-severe pain and those who have morning migraine, have a quick time to vomiting, or have failed oral triptans.
Headache The Journal of Head and Face Pain 09/2013; 53 Suppl 2(S2):62-71. DOI:10.1111/head.12181 · 2.71 Impact Factor
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