Allodynia-associated symptoms, pain intensity and time to treatment: predicting treatment response in acute migraine intervention.

OBJECTIVE: To evaluate the relationship between treatment outcomes and allodynia-associated symptoms (AAS) at the time of treatment with almotriptan. METHODS: Analyses were performed with data collected prospectively from patients in 2 recently completed early intervention trials, AXERT Early miGraine Intervention Study (AEGIS) and AXERT 12.5 mg time vs Intensity Migraine Study (AIMS): 2-hour pain free, 2-hour pain relief (AEGIS only), sustained pain free (SPF), use of rescue medication, and median headache duration (AIMS only), in the presence and absence of pretreatment AAS, which was determined by responses to a questionnaire. Analyses were conducted to evaluate possible prognostic variables. RESULTS: The presence of pretreatment AAS did not have a significant effect on 2-hour pain-free, 2-hour pain-relief or SPF rates, use of rescue medication, or headache duration. Significant factors for most favorable outcomes (greater 2-hour pain-free, 2-hour pain-relief and SPF rates, less use of rescue medication, and shorter headache duration) included treatment with almotriptan 12.5 mg, treatment of mild or moderate headache pain, and treatment within 1 hour of headache onset. CONCLUSION: Almotriptan 12.5 mg was efficacious in providing 2-hour pain free, 2-hour pain relief, SPF, and reducing rescue medication use irrespective of the presence of AAS at the time of treatment. The most optimal efficacy outcomes occurred when patients treated migraine attacks early and before the onset of severe pain. The presence of AAS, which may indicate an early phase of allodynia, did not influence the efficacy of almotriptan therapy.

Effect of pain intensity and time to administration on responsiveness to almotriptan: results from AXERT 12.5 mg Time Versus Intensity Migraine Study (AIMS).

OBJECTIVE: To determine whether time-based early treatment, independent of pain intensity, is superior to a pain intensity-based treatment, where patients are asked to treat at least moderate intensity headaches, resulting in a reduction of overall migraine headache duration. BACKGROUND: Retrospective and prospective trials have reported improved outcomes when triptans were used early or to treat mild migraine headache pain. However, tolerability as well as efficacy may be 2 of several key issues that have prevented this new treatment paradigm from becoming universally accepted. METHODS: In this multicenter, open-label, cluster-randomized study, patients with IHS-defined migraine were instructed to treat 2 sequential migraine headaches with almotriptan 12.5 mg using either Early Treatment (ET, ie, treat at earliest onset of headache pain, within 1 hour) or Standard Treatment (ST, ie, treat when headache pain intensity is moderate or severe). The novel trial design uses total migraine headache pain duration as the primary endpoint. RESULTS: Results are presented for the first headache and include an ITT population of 757 ET and 693 ST patients. Median headache duration (time from onset of headache pain until no pain) was significantly shorter in ET patients compared to ST patients (3.18 vs 5.53 hours, P < .001). An analysis of the ET subgroup treating headache pain within 1 hour of onset revealed pain intensity, ie, treating mild or moderate versus severe pain, was significantly correlated with treatment outcomes defined by total headache duration, 2-hour pain free, sustained pain free, and use of rescue medication. Multivariate analyses comparing ST subgroups that treated within 1 hour versus greater than 1 hour after headache onset, demonstrate that both pain intensity, ie, treating moderate versus severe headache pain, and treating early versus late, were significantly correlated with total headache duration, 2-hour pain free, sustained pain free, and use of rescue medication. The overall incidence of adverse events was low; nausea and dizziness were the only adverse events with an incidence > or =1% in either treatment group (nausea: 2.5% and 1.7% and dizziness 1.1% and 0.7%, in the ET and ST groups, respectively). CONCLUSION: Total headache duration was significantly shorter in the early treatment group compared to the standard treatment group. Considering time to treatment within a relatively early range of 1 hour or less, efficacy results when treating mild versus moderate pain were similar and both were associated with better outcomes than treatment of severe pain. When considering the prognostic variables of time to treatment and headache pain intensity (limited to moderate vs severe), both were independent predictors, with time to treatment a better predictor of headache duration and rescue medication use, and pain intensity a better predictor of 2-hour pain free and sustained pain free.

Adjunctive topiramate therapy in patients receiving a mood stabilizer for bipolar I disorder: a randomized, placebo-controlled trial.

OBJECTIVE: To investigate the efficacy and safety of topiramate versus placebo as adjunctive therapy for the outpatient management of bipolar I disorder. METHOD: In this 12-week, randomized, double-blind, placebo-controlled trial, adults with bipolar I disorder (DSM-IV criteria) experiencing a manic or mixed episode with a Young Mania Rating Scale (YMRS) score of >or= 18 while taking therapeutic levels of valproate or lithium received adjunctive topiramate or placebo. Topiramate was titrated from 25 to 400 mg/day over 8 weeks and was continued for 4 additional weeks. The study was conducted from October 2001 through October 2003. The primary outcome measure was the change in YMRS score from baseline to last study visit during the double-blind phase. RESULTS: The mean +/- SD change in YMRS score from baseline was -10.1 +/- 8.7 (-40.1%) in the topiramate group (N = 143) and -9.6 +/- 8.2 (-40.2%) in the placebo group (N = 144, p = .797). Greater than 50% reduction in YMRS was achieved by 39% of the topiramate group and 38% of the placebo group (p = .914). No significant treatment differences were observed for secondary efficacy measures. Compared with adjunctive placebo, adjunctive topiramate did not worsen mania or induce depression. Paresthesia, diarrhea, and anorexia were more common in the topiramate group. The topiramate group achieved greater reductions than the placebo group in body weight (-2.5 vs. 0.2 kg, p < .001) and body mass index (-0.84 vs. 0.07 kg/m(2), p < .001). CONCLUSION: In patients treated with lithium or valproate, there was no difference in the reduction of YMRS score in the topiramate and placebo groups. Both groups showed declines of 40%. Topiramate reduced body weight significantly relative to placebo without worsening depressive or manic symptoms.

Effect of cotherapy reduction on tolerability of epilepsy add-on therapy: a randomized controlled trial.

BACKGROUND: Adverse effects are the most common cause for failure of an antiepileptic drug (AED), especially when an AED is added to existing therapy. With the increased drug load, it may not be possible to titrate the newly added AED to effective doses. Reducing the dosage of AED cotherapy as the new drug is introduced may improve tolerability. OBJECTIVE: To evaluate reduction of AED cotherapy as a strategy to improve tolerability and patient retention when a new AED is added to existing therapy. METHODS: In a 20-week, randomized, open-label study, topiramate was initiated as add-on therapy in adults and adolescents (> or =12 y of age) with inadequately controlled partial-onset seizures. Patients were randomized to receive treatment in which adverse events could be managed by adjustments in AED cotherapy (flex-dose group) or treatment in which AED cotherapy dosages remained fixed (fixed-dose group). Topiramate could be adjusted as needed in both groups. In the flex-dose group, patients exited randomized treatment when topiramate was discontinued. In the fixed-dose group, patients exited when AED cotherapy was reduced due to adverse events or when topiramate was discontinued. The primary study outcome was the percentage of patients exiting randomized treatment due to adverse events. RESULTS: The flex-dose group comprised 297 patients; 302 patients were in the fixed-dose group. Significantly fewer patients in the flex-dose group exited the study due to adverse events (16% vs 23% in the fixed-dose group; p = 0.02). In the flex-dose group, 10% (17 of 168) of patients discontinued topiramate due to adverse events after AED cotherapy was reduced versus 22% (29 of 129) when AED cotherapy was not reduced. CONCLUSIONS: Reduction of AED cotherapy is a useful strategy to improve tolerability and retention when topiramate is initiated as adjunctive therapy.