Adding Additional Acute Medications to a Triptan Regimen for Migraine and Observed Changes in Headache-Related Disability: Results From the American Migraine Prevalence and Prevention (AMPP) Study.

BACKGROUND: Though triptans are the most widely used acute treatments for migraine, response to treatment is sometimes suboptimal. Triptan therapy is often augmented by the addition of other acute treatments. The benefits of this practice have not been examined in large-scale, real-world observational studies. OBJECTIVES: To assess changes in headache-related disability associated with adding additional acute treatments to a triptan regimen by category of added treatment including: a second triptan, nonsteroidal anti-inflammatory drugs (NSAID), opioids or barbiturates. METHODS: Subjects were participants in the American Migraine Prevalence and Prevention study, a longitudinal, US population-based study of individuals with "severe" headache. Respondents who met International Classification of Headache Disorders 3 beta criteria for migraine were on triptan therapy per respondent self-report, used the same triptan, and provided headache-related disability data for at least 2 consecutive years. Subjects were divided based on headache days per month into 3 groups: low-frequency episodic migraine (LFEM, 0-4), moderate-frequency episodic migraine (MFEM, 5-9), and high-frequency episodic migraine/chronic migraine (HFEM/CM, ≥ 10 headache days per month). HFEM and CM were combined into a single group for analyses because of sample size limitations. Patterns of acute treatment for migraine were monitored from one year to the next over the following couplets of years (2005-2006, 2006-2007, 2007-2008, and 2008-2009). The first eligible couplet was analyzed for each respondent. Medication regimens studied included: (1) maintaining current triptan use (consistent group); (2) adding a different triptan; (3) adding an NSAID; or (4) adding a combination analgesic containing opioids or barbiturates. We assessed change in Migraine Disability Assessment (MIDAS) score from the first to the second year of a couplet, contrasting scores of participants with consistent use with those who added an acute treatment to their triptan regimen. RESULTS: The study sample (N = 2128) included 111 individuals who added another triptan, 118 who added an opioid or barbiturate, and 69 who added an NSAID, with referent groups of approximately 600 cases in each group who remained consistent. In general, MIDAS scores were higher among those who made changes from one year to the next compared with those who did not make changes in therapy. In fully adjusted models, adding triptans or NSAIDs was associated with increased disability for HFEM/CM cases at follow-up but decreased disability at follow-up for MFEM cases, resulting in significant interaction effects for both adding triptans and NSAIDs, respectively (15.88, 95% confidence interval [CI] 0.75, 31.01, 38.52, 95% CI 12.43, 64.61). CONCLUSIONS: While the effects of adding vs staying consistent on the outcome of headache-related disability varied by medication type added and headache frequency strata, in general, these results suggest that for individuals with migraine, adding acute therapies to current triptan use is generally not associated with reductions in headache-related disability. The results were strongest among persons with HFEM and CM. These results identify important unmet medical needs in current migraine management, especially among patients with high-frequency migraine, and suggest that alternative treatment strategies are needed to improve patient outcomes.

Effects of switching acute treatment on disability in migraine patients using triptans.

OBJECTIVE: To assess the influence of switching acute treatment on headache-related disability in a population sample of individuals with migraine using acute triptan therapy. BACKGROUND: Acute treatments for migraine are often modified in clinical practice. The effect of changes in treatment from one triptan to another or from a triptan to another medication class has rarely been studied. METHODS: Patterns of acute treatment for migraine were monitored from 1 year to the next in the American Migraine Prevalence and Prevention (AMPP) Study for the following couplets (2005-2006, 2006-2007, 2007-2008, and 2008-2009). Changes in medication regimens were classified as follows: (1) switch within the triptan class; (2) switch to combination analgesics containing opioids or barbiturates; (3) switch to non-steroidal anti-inflammatory drug (NSAID) agents; (4) maintaining current therapy (consistent use, "control"). We assessed change in migraine disability assessment scale score from the first to the second year of a couplet contrasting those with consistent use with those who changed acute treatment. Each individual contributed only 1 couplet to the analysis. Persons who added an acute treatment are considered in a separate manuscript. We modeled change in migraine disability assessment scale score as a function of change in medication regimen with consistent users as the control group. RESULTS: We identified 81 individuals who switched to another triptan, with a referent of 619 who remained consistent, 31 cases who switched to an opioid or barbiturate with a referent of 666 who remained consistent, and 20 cases who switched to an NSAID with a referent of 667 cases who remained consistent. In cell-mean coded analyses of covariance (ANCOVA), switching from one triptan to another or switching from a triptan to an opioid/barbiturate was never associated with significant improvements in headache-related disability compared with consistent treatment. Switching from a triptan to an NSAID was associated with significant increases in headache-related disability among those with high-frequency episodic/chronic migraine (HFEM/CM) compared with those with low-frequency episodic migraine (LFEM) (interaction = 34.81, 95% confidence interval 10.61 to 59.00). The same was true comparing high-frequency episodic/chronic migraine with those with moderate-frequency episodic migraine (interaction = 48.73, 95% confidence interval 2.63 to 94.83). CONCLUSIONS: In this observational study, switching triptan regimens does not appear to be associated with improvements in headache-related disability and in some cases is associated with increased headache-related disability.

Medullary pain facilitating neurons mediate allodynia in headache-related pain.

OBJECTIVE: To develop and validate a model of cutaneous allodynia triggered by dural inflammation for pain associated with headaches. To explore neural mechanisms underlying cephalic and extracephalic allodynia. METHODS: Inflammatory mediators (IM) were applied to the dura of unanesthetized rats via previously implanted cannulas, and sensory thresholds of the face and hind-paws were characterized. RESULTS: IM elicited robust facial and hind-paw allodynia, which peaked within 3 hours. These effects were reminiscent of cutaneous allodynia seen in patients with migraine or other primary headache conditions, and were reversed by agents used clinically in the treatment of migraine, including sumatriptan, naproxen, and a calcitonin gene-related peptide antagonist. Consistent with clinical observations, the allodynia was unaffected by a neurokinin-1 antagonist. Having established facial and hind-paw allodynia as a useful animal surrogate of headache-associated allodynia, we next showed that blocking pain-facilitating processes in the rostral ventromedial medulla (RVM) interfered with its expression. Bupivacaine, destruction of putative pain-facilitating neurons, or block of cholecystokinin receptors prevented or significantly attenuated IM-induced allodynia. Electrophysiological studies confirmed activation of pain-facilitating RVM "on" cells and transient suppression of RVM "off" cells after IM. INTERPRETATION: Facial and hind-paw allodynia associated with dural stimulation is a useful surrogate of pain associated with primary headache including migraine and may be exploited mechanistically for development of novel therapeutic strategies for headache pain. The data also demonstrate the requirement for activation of descending facilitation from the RVM for the expression of cranial and extracranial cutaneous allodynia, and are consistent with a brainstem generator of allodynia associated with headache disorders.