David Millson

Psychological, Sleep, Lifestyle, and Comorbid Associations With Headache

Objective.—To investigate the associations of headache occurrence, severity, and frequency with psychological, sleep, and lifestyle characteristics, and comorbid conditions.

Epidemiology of headache in an English district

Headache prevalence, characteristics and impact in adults were measured using a cross-sectional general population survey in North Staffordshire, UK. A postal survey was mailed out to 4885 adults (aged ≥ 18 years) with an adjusted response rate of 56% (n = 2662). Of respondents 93% reported headache ever and 70% in the last 3 months. Women and younger people reported higher headache prevalences. Of those reporting headache in the last 3 months, 23% experienced headache at least weekly and 16% experienced severe headache pain. Headaches affected work, home or social activities in 43% of sufferers and 20% reported at least moderate headache-related disability. Higher levels of disability were associated with higher levels of pain, 61% with severe disability reporting severe pain compared with 13% who had mild or moderate disability. In the total adult population sample headache affected more than two-thirds in the last 3 months and 14% of all adults reported headache-related disability of at least moderate level, which translates to a large burden in the general population.

Cost-effectiveness analysis of stratified versus stepped care strategies for acute treatment of migraine: The Disability in Strategies for Care (DISC) Study.

AbstractBackground: The Disability in Strategies for Care (DISC) study was the first large randomised controlled trial to compare alternative treatment strategies in the acute treatment of migraine. With 835 patients in its intention-to-treat efficacy analysis, DISC compared a stratified care strategy, where initial therapy was based on clinical need as determined by the Migraine Disability Assessment Scale (MIDAS) and two stepped care strategies (across attacks and within attacks), where first-line therapy with a simple combination analgesic was escalated, if response had been inadequate, to zolmitriptan, a migraine-specific therapy. Objective: To report on the cost effectiveness of these three strategies from a societal perspective. Study design and methods: A cost-effectiveness analysis was undertaken using data from the DISC study, and including both health service and productivity costs. Data were collected prospectively on drug usage (main therapy and rescue medication); resource use associated with adverse events was estimated by a clinician blinded to treatment strategy. Health service resource use was costed using UK unit costs (1999 to 2000 values). Data were collected using diary cards on the amount of time patients lost from work, and on reduced effectiveness at work, due to a migraine attack. This facilitated an estimate of the productivity costs associated with the treatment strategies. To assess cost effectiveness, the differences in costs between the strategies were related to the two primary outcome measures in the trial: headache response 2 hours after initial therapy and disability-adjusted time during the first 4 hours after initial therapy. Results: Although the mean health service cost was higher in the stratified care group (mean over 6 attacks of £28.25 versus £11.74 and £23.15 in the stepped care across attacks group and within attacks group, respectively), mean productivity costs over 6 attacks were lower in the stratified group (£112.22 versus £144.70 and £127.53). The total mean cost over six attacks was, therefore, lowest in the stratified care group (£138.95 compared with £157.19 in the stepped care across attacks group and £148.53 in the stepped care within attacks group), although these differences did not reach statistical significance. In terms of headache response, stratified care was statistically significantly more effective than both forms of stepped care. Using disability-adjusted time, stratified care was statistically significantly more effective than stepped care across attacks, but not against stepped care within attacks. Conclusion: Given its lower mean costs and higher mean effectiveness, a stratified care strategy, which included zolmitriptan, was the dominant strategy and was unequivocally more cost effective from a societal perspective than either stepped care strategy. When the uncertainty around these means was considered, stratified care had the highest probability of being cost effective.

Safety profile of the triptans

The triptans are 5-HT1B/1D agonists used as migraine and cluster-specific agents. Seven are in commercial use worldwide; in order of release these are sumatriptan, zolmitriptan, rizatriptan, naratriptan, almotriptan, frovatriptan and eletriptan. Sumatriptan has been in clinical use since 1991, and although postmarketing studies have stimulated much debate of triptan strengths and weaknesses, their overall safety profile appears excellent. The most serious adverse events are cardiovascular, due to coronary artery narrowing as a consequence of coronary artery 5-HT1B receptor activity. Triptans are contraindicated in patients with vascular disease. Other events are even more rare, and include the potential for drug–drug interactions, based on metabolic elimination pathways. Serotonin syndrome has been a concern, but one large prospective study failed to document a single case, and reports are sporadic and not clearly causative.

The Natural History of Headache: Predictors of Onset and Recovery

The objective of this study was to determine predictors of onset of new headache episodes and recovery from headache over one year. A population-based cohort study was conducted, comprising a baseline postal survey to a random sample of adults aged ≥18 years, with follow-up survey after 1 year. Risk factor data at baseline were compared with headache status at follow-up in two groups: (i) those free of recent headache at baseline and (ii) those with a recent headache at baseline. In respondents free of recent headache at baseline, previous headache [risk ratio (RR) 4.15], the presence of other pain at baseline (RR 1.43), severe sleep problems (RR 1.67) and drinking caffeine (RR 1.99) increased the risk of a new headache episode during the follow-up year. In respondents with recent headache at baseline, less severe headaches at baseline predicted recovery during the follow-up year, as did the absence of anxiety [recovery ratio (ReR) 2.84] and of sleep problems (ReR 2.77). Risks for increased headache-related disability reflected those for onset of a new episode and these risks increased in strength for large increases in disability. Sleep problems and caffeine consumption increase the risk of developing headache and thus provide targets for prevention. Low levels of anxiety, sleep problems and the absence of other pain improve the likelihood of recovering and remaining free from headache.

Prevalence of comorbid psychiatric illness and substance misuse in primary care in England and Wales

Study objective: To estimate the annual period prevalence of co-occurring psychiatric illness and substance misuse among patients in primary care. Design: Analysis of the general practice research database. Setting: England and Wales, 1993–1998. Participants: Registered patients at 230 general practices representing 3.1% of the population. A comorbid case was defined as one with both a psychiatric diagnosis and substance misuse diagnosis (not including alcohol or tobacco) within a calendar year. A potentially chronic comorbid case was one that met this definition and, in addition, was treated in subsequent years for either a psychiatric condition or substance misuse. Main results: The annual period prevalence of comorbidity increased from 50/100 000 patient years of exposure (PYE) to 80/100 000 PYE, an increase of 62% during the study period. Rates of comorbid psychoses, comorbid schizophrenia, and comorbid paranoia increased by 147%, 128%, and 144%. The average age of comorbid cases decreased from 38 years to 34 years. Over 80% of comorbid cases were newly diagnosed in each study year, although many are treated in subsequent years for either psychiatric illness or substance misuse. Conclusions: This study provides data on the nature and extent of comorbidity in primary care in England and Wales. As the comorbidity rate is increasing by about 10% each year, and as comorbid cases are becoming younger, it is probable that the comorbidity rate will have increased beyond the study end point.

Substance misuse and psychiatric illness: prospective observational study using the general practice research database

Objectives: To quantify the relation between substance misuse and psychiatric illness in the UK general practice population in terms of (a) the relative risk of developing one condition given prior exposure to the other and (b) the proportion of cases of one condition attributable to exposure to the other. Design: Population based prospective observational study using the general practice research database (GPRD) between 1993 and 1998. The 230 GP practices represent 3.1% of the population. Setting: England and Wales. Participants: 1.4 million registered patients of whom 3969 had both substance misuse and psychiatric diagnoses between 1993 and 1998. Main outcome measures: Relative risk (RR) for subsequent psychiatric illness among participants exposed to substance misuse and RR for subsequent substance misuse among participants exposed to psychiatric illness. Population attributable risk (PAR) of psychiatric illness attributable to substance misuse and of substance misuse attributable to psychiatric illness. Results: The baseline prevalence of psychiatric illness over the study period was 15% and 0.3% for substance abuse. RR for psychiatric illness for substance misusers compared with non-substance misusers was 1.54 (95% CI 1.47 to 1.62). RR for substance misuse among psychiatric compared with non-psychiatric cases was 2.09 (95% CI 1.99 to 2.22). PAR for psychiatric illness attributable to substance misuse was 0.2%. PAR for substance misuse attributable to psychiatric illness was 14.2%. Discussion: Only a comparatively small proportion of psychiatric illness seems possibly attributable to substance use whereas a more substantial proportion of substance use seems possibly attributable to psychiatric illness. This study does not support the hypotheses that comorbidity between substance misuse and psychiatric illness is primarily the result of substance misuse or that increasing comorbidity is largely attributable to increasing substance misuse.

Zolmitriptan versus sumatriptan for the acute oral treatment of migraine: a randomized, double-blind, international study

This randomized, double‐blind, parallel‐group study compared the efficacy and tolerability of zolmitriptan (2.5 or 5 mg) and sumatriptan (50 mg) in the acute oral treatment of up to six moderate‐to‐severe migraine attacks. The intention to treat (ITT) population comprised of 1522 patients: 500 treated with zolmitriptan 2.5 mg (2671 attacks), 514 with zolmitriptan 5 mg (2744 attacks) and 508 with sumatriptan 50 mg (2693 attacks). Overall, the 2‐h headache response rates in these groups were 62.9, 65.7 and 66.6%, respectively. There were no statistically significant differences between sumatriptan 50 mg and zolmitriptan 2.5 mg (P=0.12) or 5 mg (P=0.80). Approximately 40% of patients in each group reported a 2‐h headache response in ≥ 80% of attacks. There were no statistically significant differences between the groups in the rates of headache response at 1 h (zolmitriptan 2.5 mg 36.9%, zolmitriptan 5 mg 39.5% and sumatriptan 50 mg 38.0%) or 4 h (70.3, 72.9 and 72.2%, respectively) or in the rates of meaningful migraine relief at 1, 2 or 4 h or sustained (24‐h) pain relief. All treatments were well tolerated. In conclusion, zolmitriptan (2.5 or 5 mg) proved similarly efficacious compared with sumatriptan (50 mg), both in terms of response rates and consistency across attacks.

Migraine pharmacotherapy with oral triptans: a rational approach to clinical management

The recent clinical development of a number of migraine specific 5-HT1B/1Dagonist triptans with enhanced lipophilicity (TELs), relative to the first drug of this class sumatriptan, and with a range of different metabolic, pharmacokinetic and receptor affinity profiles, provides the potential for critically different clinical profiles. Eletriptan, naratriptan, rizatriptan and zolmitriptan display both increased stability to first pass metabolic inactivation by monoamine oxidase (MAO-A) and enhanced lipophilicity (4- to >> 120-fold more than sumatriptan), leading to increased oral bioavailability (2- to 5-fold more than the 14% reported for oral sumatriptan). Central penetration and increased receptor affinity and selectivity for the neuronal (5-HT1D) receptor also combine to allow for lower total oral dosing (i.e., unit doses of 15 mg or less compared with 50 - 300 mg doses of sumatriptan) and reduced peripheral exposure to the coronary vasoconstrictor (5-HT1B) receptor. The notable exception being eletriptan, where an active P-glycoprotein blood-brain barrier efflux system effectively negates these benefits and requires an 80 mg oral dose. Differences in the metabolic balance between hepatic P450 (especially CYP 1A2) and MAO-A inactivation lead to potential drug interactions for all TELs with the oral contraceptive pill (OCP), fluvoxamine and the quinilone antibiotics (with increased triptan levels). An important but complex MAO-A interaction between a metabolite of propranolol and rizatriptan mandates dosage reduction (to 5 mg) for rizatriptan in the presence of propranolol treatment. There is also an absolute contraindication for the concurrent administration of the MAO-A inhibitor moclobemide and rizatriptan. All the new-marketed TELs have potential clinical benefits and were well-tolerated relative to sumatriptan. Both rizatriptan (10 mg) and zolmitriptan (2.5 mg and 5 mg) demonstrate at least equivalent efficacy to sumatriptan 25, 50 and 100 mg, respectively, making them suitable first line agents for moderate or severe migraine headaches. Rizatriptan has the fastest onset of effect of the TELs. Naratriptan would appear to have lower recurrent headache rate than sumatriptan, rizatriptan or zolmitriptan. Therefore, for headaches of long duration and with a tendency to recur naratriptan may be the most appropriate treatment. Thus, knowledge of the metabolic, pharmacokinetic and clinical profiles of the TELs facilitates the selection of a triptan which allows optimisation of the clinical benefits for individual patients, minimising the risk of drug interactions and a minimally effective dose to reduce potential adverse events (AEs).

Upper Gastroduodenal Ulceration in Arthritis Patients Treated with Celecoxib

OBJECTIVE: To evaluate the comparative incidence of endoscopic gastroduodenal ulcers in patients with rheumatoid arthritis or osteoarthritis treated with celecoxib. DESIGN: Quantitative systematic review of randomized controlled trials. SUBJECTS: Patients (n = 4632) with rheumatoid arthritis or osteoarthritis reported in five trials. MAIN OUTCOME MEASURES: Rate ratios, rate differences, and the number needed to harm were calculated for the incidence of endoscopically documented gastroduodenal ulcers. RESULTS: Pooled rate ratios (RRs) relative to placebo for endoscopic ulcers at 12 weeks were 1.96 (95% CI 0.85 to 4.55) for celecoxib 100 mg twice daily and 2.35 (95% CI 1.02 to 5.38) for celecoxib 200 mg twice daily. There was no significant difference in gastroduodenal ulcers at 12 weeks between celecoxib 200 mg twice daily and celecoxib 100 mg twice daily; the corresponding pooled RR was 1.21 (95% CI 0.62 to 2.38). In contrast, celecoxib 200 mg twice daily was associated with a significantly lower rate of gastroduodenal ulcers than was naproxen 500 mg twice daily at 12 weeks (RR 0.24; 95% CI 0.17 to 0.33). On average, for every seven patients treated with naproxen, one more had an endoscopic ulcer than if they were treated with celecoxib. Celecoxib 200 mg twice daily also had a significantly lower risk of endoscopic ulcers than did either modified-release diclofenac 75 mg twice daily at 24 weeks (RR 0.24; 95% CI 0.11 to 0.52) or ibuprofen 800 mg three × daily at 12 weeks (RR 0.30; 95% CI 0.20 to 0.46). CONCLUSIONS: Endoscopic studies have shown that celecoxib, at a wide range of doses, is associated with a lower incidence of gastroduodenal ulcers than are diclofenac, ibuprofen, or naproxen. The incidence rates of gastroduodenal ulcers associated with celecoxib were similar, although not equivalent, to placebo. Head-to-head comparisons suggest that, at the wide range of doses studied (100–800 mg/d), there are no dose-related increases in endoscopic gastroduodenal ulcers with celecoxib. The results of longer term comparative trials of celecoxib based on clinical outcomes are needed to determine celecoxibs ultimate risk—benefit profile.