Blindness and bias in a trial of antidepressant medication for chronic tension-type headache.

This study aimed to examine penetration of the blind in a randomized, placebo-controlled trial. Neurologists' ratings of improvement and medication side-effects, participants' ratings of improvement and daily diary recordings of headaches were assessed along with participants' and neurologists' guesses about treatment group placement in participants who completed at least 3 months of treatment (N = 169). Despite blinding, treating neurologists successfully identified the medication condition for 82% of participants receiving medication only; trial participants accurately identified their medication condition when receiving active medication (77% of participants), but not when receiving placebo. Concurrent stress-management therapy reduced, but did not eliminate penetration of the blind. Irrespective of drug condition, when participants were improved they were judged to be on active medication and when unimproved they were judged to be on placebo. However, neurologists' ratings of improvement, participants' reports of improvement and daily headache recordings yielded equivalent outcomes. Penetration of the blind needs to be assessed, not assumed in clinical trials in headache. However, penetration of the blind did not produce a prodrug bias as has been asserted by critics. Better methods of assessing and quantifying blindness are needed.

Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial.

CONTEXT: Chronic tension-type headaches are characterized by near-daily headaches and often are difficult to manage in primary practice. Behavioral and pharmacological therapies each appear modestly effective, but data are lacking on their separate and combined effects. OBJECTIVE: To evaluate the clinical efficacy of behavioral and pharmacological therapies, singly and combined, for chronic tension-type headaches. DESIGN AND SETTING: Randomized placebo-controlled trial conducted from August 1995 to January 1998 at 2 outpatient sites in Ohio. PARTICIPANTS: Two hundred three adults (mean age, 37 years; 76% women) with diagnosis of chronic tension-type headaches (mean, 26 headache d/mo). INTERVENTIONS: Participants were randomly assigned to receive tricyclic antidepressant (amitriptyline hydrochloride, up to 100 mg/d, or nortriptyline hydrochloride, up to 75 mg/d) medication (n = 53), placebo (n = 48), stress management (eg, relaxation, cognitive coping) therapy (3 sessions and 2 telephone contacts) plus placebo (n = 49), or stress management therapy plus antidepressant medication (n = 53). MAIN OUTCOME MEASURES: Monthly headache index scores calculated as the mean of pain ratings (0-10 scale) recorded by participants in a daily diary 4 times per day; number of days per month with at least moderate pain (pain rating >/=5), analgesic medication use, and Headache Disability Inventory scores, compared by intervention group. RESULTS: Tricyclic antidepressant medication and stress management therapy each produced larger reductions in headache activity, analgesic medication use, and headache-related disability than placebo, but antidepressant medication yielded more rapid improvements in headache activity. Combined therapy was more likely to produce clinically significant (>/=50%) reductions in headache index scores (64% of participants) than antidepressant medication (38% of participants; P =.006), stress management therapy (35%; P =.003), or placebo (29%; P =.001). On other measures the combined therapy and its 2 component therapies produced similar outcomes. CONCLUSIONS: Our results indicate that antidepressant medication and stress management therapy are each modestly effective in treating chronic tension-type headaches. Combined therapy may improve outcome relative to monotherapy.

Exteroceptive suppression periods and pericranial muscle tenderness in chronic tension-type headache: effects of psychopathology, chronicity and disability.

We examined pericranial muscle tenderness and abnormalities in the second exteroceptive suppression period (ES2) of the temporalis muscle in chronic tension-type headache (CTTH; n = 245) utilizing a blind design and methods to standardize the elicitation and scoring of these variables. No ES2 variable differed significantly between CTTH sufferers and controls (all tests, P>0.05). We found no evidence that CTTH sufferers with daily or near daily headaches, a mood or an anxiety disorder, or high levels of disability exhibit abnormal ES2 responses (all tests, P>0.05). CTTH sufferers were significantly more likely than controls to exhibit pervasive tenderness in pericranial muscles examined with standardized (500 g force) manual palpation (P<0.005). Female CTTH sufferers exhibited higher levels of pericranial muscle tenderness than male CTTH sufferers at the same level of headache activity (P<0.0001). Elevated pericranial muscle tenderness was associated with a comorbid anxiety disorder. These findings provide further evidence of pericranial hyperalgesia in CTTH and suggest this phenomenon deserves further study. Basic research that better elucidates the biological significance of the ES2 response and the factors that influence ES2 assessments appears necessary before this measure can be of use in clinical research.

Enhancing the effectiveness of relaxation-thermal biofeedback training with propranolol hydrochloride.

This article evaluated the ability of propranolol to enhance results achieved with relaxation-biofeedback training. Thirty-three patients were randomized to relaxation-biofeedback training alone (administered in a limited-contact treatment format), or to relaxation-biofeedback training accompanied by long-acting propranolol (with dosage individualized at 60, 120, or 180 mg/day). Concomitant propranolol therapy significantly enhanced the effectiveness of relaxation-biofeedback training when either daily headache recordings (79% vs. 54% reduction in migraine activity) or neurologist clinical evaluations (90% vs. 66% reduction) were used to assess treatment outcome. Concomitant propranolol therapy also yielded larger reductions in analgesic medication use and greater improvements of quality of life measures than relaxation-biofeedback training alone but was more frequently associated with side effects.

A comparison of pharmacological (amitriptyline HCL) and nonpharmacological (cognitive-behavioral) therapies for chronic tension headaches.

Forty-one recurrent tension headache sufferers were randomly assigned to either cognitive-behavioral therapy (administered in a primarily home-based treatment protocol) or to amitriptyline therapy (with dosage individualized at 25, 50, or 75 mg/day). Cognitive-behavioral therapy and amitriptyline each yielded clinically significant improvements in headache activity, both when improvement was assessed with patient daily recordings (56% and 27% reduction in headache index, respectively), and when improvement was assessed with neurologist ratings of clinical improvement (94% and 69% of patients rated at least moderately improved, respectively). In instances where differences in treatment effectiveness were observed (headache index, somatic complaints, perceptions of control of headache activity), cognitive-behavioral therapy yielded somewhat more positive outcomes than did amitriptyline. Neither treatment, however, eliminated headache problems.

Propranolol in the management of recurrent migraine: a meta-analytic review.

We used meta-analytic statistical techniques to synthesize findings from studies that evaluated propranolol HCI for the prevention of recurrent migraine (2,403 treated patients). The modal migraine sufferer treated in these studies was a female, about 37 years of age, who suffered from common (rather than classical) migraines and reported a 17-year history of problem migraines. The modal treatment was 160 mg. propranolol per day. Meta-analysis revealed that, on average, propranolol yielded a 44% reduction in migraine activity when daily headache recordings were used to assess treatment outcome, and a 65% reduction in migraine activity when less conservative measures (e.g., clinical ratings of improvement, global patient reports) were used. Meta-analysis thus revealed substantial support for short-term effectiveness of propranolol. However, little information was available concerning the long-term effectiveness of propranolol.

Long-term maintenance of improvements achieved with (abortive) pharmacological and nonpharmacological treatments for migraine: preliminary findings.

This report presents the first prospective comparison of the long-term maintenance of reductions in recurrent migraine headaches achieved with (abortive) pharmacological and nonpharmacological (combined relaxation training and thermal biofeedback training) treatments. Nineteen of 21 (90%) successfully treated patients (50% or greater reduction in headache activity) were contacted for follow-up evaluation 3 years later. Migraine sufferers who had been treated with ergotamine were less likely to still be relying on the treatment they had received and more likely to have additional medical treatment for their headaches and to be using prophylactic or narcotic medication than were migraine sufferers who had been treated with relaxation/biofeedback training. However, daily headache recordings revealed that patients in both treatment groups continued to show lower headache activity at 3-year follow-up than prior to treatment. Although preliminary, these findings raise the possibility that improvements achieved with nonpharmacological treatment are more likely to be maintained without additional treatment than are similar improvements achieved with abortive pharmacological treatment.

Enhancing the effectiveness of abortive therapy: a controlled evaluation of self-management training.

Research suggests that approximately one half of recurrent headache sufferers fail to adhere properly to drug treatment regimens with as many as two thirds of patients failing to make optimal use of abortive medications such as ergotamine. In spite of these findings there are no controlled studies that have attempted to evaluate methods for improving adherence to drug regimens for the treatment of chronic headache disorders. In an initial effort to address this adherence problem thirty-four recurrent migraine sufferers were randomized to abortive therapy with ergotamine tartrate plus caffeine (standard abortive therapy) or to standard abortive therapy accompanied by a brief educational intervention designed to facilitate the migraine sufferer's effective use of ergotamine. Patients who received the adjunctive educational intervention attempted to abort a greater percentage of their migraine attacks (70% vs 40%) and showed larger reduction in headache activity (e.g., 40% vs 26% reduction in month two of treatment). However, patients in both treatment groups used similar amounts of abortive medication when attempting to abort a migraine attack and showed similar reductions in analgesic medication use with abortive therapy. There results suggest that brief educational interventions designed to address the problem of patient adherence may yield significant improvements in standard therapies. We argue that such educational interventions deserve more attention in the headache treatment literature than they have received to date.

Non-cholinergic synaptic excitation in neostriatum: pharmacological evidence for mediation by a glutamate-like transmitter.

We studied the synaptic pharmacology of an excitatory pathway in the neostriatum using electrophysiological techniques in tissue slices from rats. In response to single electrical stimuli, two negative, extracellular potentials (N-1 and N-2) were recorded through micropipette electrodes within 150-450 micron of the stimulating cathode. N-2 was reversibly reduced or abolished by reducing the concentration of calcium in the bathing medium, while N-1 was unaffected. Both N-1 and N-2 were reversibly abolished by the local anaesthetic procaine. Single-unit, extracellular action potentials were, at times, associated with either N-1 or N-2. Intracellular recordings showed action potentials at N-2 latency arising from graded, monophasic, depolarizing potentials. Bath-applied cholinoceptor and dopamine receptor antagonists failed to reduce N-2. By contrast, antagonists of excitatory amino acid transmitters reversibly reduced or abolished N-2. gamma-D-Glutamylglycine (GG), (+/-)-cis-2,3-piperidine dicarboxylic acid (PDA) and DL-2-amino-4-phosphonobutyric acid (APB) blocked N-2 with ED50S of 0.79 mM, 1.0 mM and 1.1 mM, respectively. (-)-Baclofen reversibly blocked N-2 with an ED50 of 0.79 microM; (+)-baclofen was 330 times less potent. The results suggest that N-1 results from direct activation of fibre tracts or cell bodies, while N-2 is a population spike mediated by excitatory synapses whose natural transmitter pharmacologically resembles glutamate.

The clearing of excess potassium from extracellular space in spinal cord and cerebral cortex.

The relative importance of active and passive transport processes in the clearing of potassium released from active neurons was estimated Extracellular potassium activity [K+]0 was measured with ion-selective microelectrodes in the sensory area of the neocortex and in lumbosacral spinal cord of cats. Transient elevation of [K+]0 was evoked in cortex by stimulation of VPL and in spinal cord by stimulation of afferent nerves. The rate with which excess [K+]0 was cleared was either feebly or not at all influenced by variation of the intensity and frequency of stimulation. The half-decay times of [K+]0 were however prolonged when the duration of stimulus trains was increased. Only small differences were seen in the rate of decay of [K+]0 transients recorded at different locations within the gray matter; the shortest half-decay times occurred where K+ responses were largest. The different profiles of distribution of delta [K+]0 in response to stimulation of the cortical surface and of VPL nucleus were mapped. As in spinal cord also in cortex the distribution of the evoked sustained shifts of electric potential mirrored the distribution of [K+]0 transients. The rate at which K+ could diffuse out of volume sources similar in magnitude to the volumes of distribution of [K+]0 responses in gray matter were calculated. The observed half-decay times of [K+]0 transients were more than a hundred times shorter than those calculated for diffusion either in spinal cord or in cortex. Intravenous administration of digitoxigenin was shown to retard the clearing of [K+]0 and caused an elevation of the unstimulated [K+]0 baseline. Seizures were frequently induced by digitoxigenin when the [K+]0 baseline was only slightly elevated, and the occurrence of seizures was not associated with a definable threshold level of [K+]0. It is concluded that active reuptake is the principal mechanism of the clearing of [K+]0 released by neurons. Redistribution of K+ by diffusion must have been negligible under the conditions of these experiments, but may be more important when only a few neurons release K+ amongst many inactive cells. Considerations of a glial transport network are probably inconsequential for theories of the generation of seizures.