IMPORTANCE Early, safe, effective, and durable evidence-based interventions for children and adolescents with chronic migraine do not exist.OBJECTIVE To determine the benefits of cognitive behavioral therapy (CBT) when combined with amitriptyline vs headache education plus amitriptyline. DESIGN, SETTING, AND PARTICIPANTSA randomized clinical trial of 135 youth (79% female) aged 10 to 17 years diagnosed with chronic migraine (Ն15 days with headache/month) and a Pediatric Migraine Disability Assessment Score (PedMIDAS) greater than 20 points were assigned to the CBT plus amitriptyline group (n = 64) or the headache education plus amitriptyline group (n = 71). The study was conducted in the Headache Center at Cincinnati Children's Hospital between October 2006 and September 2012; 129 completed 20-week follow-up and 124 completed 12-month follow-up.INTERVENTIONS Ten CBT vs 10 headache education sessions involving equivalent time and therapist attention. Each group received 1 mg/kg/d of amitriptyline and a 20-week end point visit. In addition, follow-up visits were conducted at 3, 6, 9, and 12 months. MAIN OUTCOMES AND MEASURESThe primary end point was days with headache and the secondary end point was PedMIDAS (disability score range: 0-240 points; 0-10 for little to none, 11-30 for mild, 31-50 for moderate, >50 for severe); both end points were determined at 20 weeks. Durability was examined over the 12-month follow-up period. Clinical significance was measured by a 50% or greater reduction in days with headache and a disability score in the mild to none range (<20 points).RESULTS At baseline, there were a mean (SD) of 21 (5) days with headache per 28 days and the mean (SD) PedMIDAS was 68 (32) points. At the 20-week end point, days with headache were reduced by 11.5 for the CBT plus amitriptyline group vs 6.8 for the headache education plus amitriptyline group (difference, 4.7 [95% CI, 1.7-7.7] days; P = .002). The PedMIDAS decreased by 52.7 points for the CBT group vs 38.6 points for the headache education group (difference, 14.1 [95% CI, 3.3-24.9] points; P = .01). In the CBT group, 66% had a 50% or greater reduction in headache days vs 36% in the headache education group (odds ratio, 3.5 [95% CI, 1.7-7.2]; P < .001). At 12-month follow-up, 86% of the CBT group had a 50% or greater reduction in headache days vs 69% of the headache education group; 88% of the CBT group had a PedMIDAS of less than 20 points vs 76% of the headache education group. Measured treatment credibility and integrity was high for both groups.CONCLUSIONS AND RELEVANCE Among young persons with chronic migraine, the use of CBT plus amitriptyline resulted in greater reductions in days with headache and migraine-related disability compared with use of headache education plus amitriptyline. These findings support the efficacy of CBT in the treatment of chronic migraine in children and adolescents.

Synthetic oligonucleotides were used to screen a rat striatal cDNA library for sequences corresponding to the tachykinin peptides substance P and neurokinin A. The cDNA library was constructed from RNA isolated from the rostral portion of the rat corpus striatum, the site of striatonigral cell bodies. Two types of cDNAs were isolated and dermed by restriction enzyme analysis and DNA sequencing to encode both substance P and neurokinin A. The two predicted preprotachykinin protein precursors (130 and 115 amino acids in length) differ from each other by a pentadecapeptide sequence between the two tachykinin sequences, and both precursors possess appropriate processing signals for substance P and neurokinin A production. The presence of a third preprotachykinin mRNA of minor abundance in rat striatum was established by S1 nuclease protection experiments. This mRNA encodes a preprotachykinin of 112 amino acids containing substance P but not neurokinin A. These three mRNAs are derived from one rat gene as a result of differential RNA processing; thus, this RNA processing pattern further increases the diversity of products that can be generated from the preprotachykinin gene.Of all the naturally occurring neuropeptides, the undecapeptide substance P (SP) is perhaps the peptide best documented as a neurotransmitter and/or neuromodulator substance in both central and peripheral nervous systems (1, 2). SP belongs to a family of structurally related peptides, the tachykinins. Peptides in this family include neurokinin A (NKA, also known as substance K) and neurokinin B (see ref.3 for discussion); they all exhibit similar biological activities-including contraction of smooth muscle and hypotension-and share a common COOH-terminal sequence, PheXaa-Gly-Leu-Met-NH2 but possess distinct NH2-terminal sequences that convey receptor specificities.Little is known about the biosynthesis of the tachykinins and the regulation ofpreprotachykinin (PPT) gene expression (4). Nawa et al. (5) have recently cloned cDNAs that correspond to two types of bovine PPT mRNAs (a and /3) that are derived from one gene (5, 6). Because most information about the localization and functions of the tachykinins and their receptors has involved the rat nervous system, it is the system of choice for an analysis of tachykinin gene expression. It is important to identify the primary structure of rat PPT mRNAs, the precursor proteins encoded by these mRNAs, and the specific gene(s) encoding the PPT mRNAs as well as to understand its regulation. The development of a specific and sensitive assay for individual PPT mRNAs is also necessary. We report here progress made toward these goals, describing three rat PPH mRNAs that encode SP and NKA derived from a single gene; differential RNA processing yields the structural differences of these peptide precursors. A preliminary account of this work has appeared (7). (Holtzmann, Madison, WI) was used for RNA isolation by the guanidine isothiocyanate method (9). Poly(A)+ RNA was isolated using oligo(dT)-cellulos...

The implications for treatment of chronic pain in children are discussed with an emphasis on greater attention to developmental issues and their relation to coping, emotional functioning, and disability in pediatric pain. Further research examining differences in coping and disability between different pediatric pain groups is also warranted.

Abstract-Objective:To review evidence on the pharmacologic treatment of the child with migraine headache. Methods: The authors reviewed, abstracted, and classified relevant literature. Recommendations were based on a four-tiered scheme of evidence classification. Treatment options were separated into medications for acute headache and preventive medications. Results: The authors identified and reviewed 166 articles. For acute treatment, five agents were reviewed. Sumatriptan nasal spray and ibuprofen are effective and are well tolerated vs placebo. Acetaminophen is probably effective and is well tolerated vs placebo. Rizatriptan and zolmitriptan were safe and well tolerated but were not superior to placebo. For preventive therapy, 12 agents were evaluated. Flunarizine is probably effective. The data concerning cyproheptadine, amitriptyline, divalproex sodium, topiramate, and levetiracetam were insufficient. Conflicting data were found concerning propranolol and trazodone. Pizotifen, nimodipine, and clonidine did not show efficacy. Conclusions: For children (Ͼage 6 years), ibuprofen is effective and acetaminophen is probably effective and either can be considered for the acute treatment of migraine. For adolescents (Ͼ12 years of age), sumatriptan nasal spray is effective and should be considered for the acute treatment of migraine. For preventive therapy, flunarizine is probably effective and can be considered, but is not available in the United States. There are conflicting or insufficient data to make any other recommendations for the preventive therapy of migraine in children and adolescents. For a clinical problem so prevalent in children and adolescents, there is a disappointing lack of evidence from controlled, randomized, and masked trials.