Commentary—Could Prazosin Play a Role in Treating Chronic Posttraumatic Headache?

Headache is a common symptom after any severity traumatic brain injury in the civilian and military populations. Currently, there is no evidence-based treatment protocol for posttraumatic headache, and management largely is based on therapies used in the primary headache disorders.

There is a complex interaction between mood disorders, posttraumatic stress disorder (PTSD), sleep disorders, and headache. Depression and PTSD are frequently seen in civilian and military populations accompanying chronic posttraumatic headache. In civilians, about one-third of patients with posttraumatic headache meet criteria for depression and PTSD. A longitudinal study of Iraq and Afghanistan veterans followed over three years found that co-occurrence of depression, PTSD, or both would increase the risk of chronic posttraumatic headache more than TBI alone. Another meta-analysis of civilian and military TBI found that, though PTSD could affect intensity and severity of chronic posttraumatic headache, TBI was an independent risk factor for chronic posttraumatic headache. PTSD and depression can cause sleep disruption and intensify pain syndromes, including headache.

Sylvia Lucas, MD, PhD

Though prazosin had been shown to be effective in decreasing nightmares, improving sleep, or decreasing daytime sleepiness in many prior studies, the PACT trial, a randomized, double-blind controlled trial of 304 participants at Veterans Affairs medical centers, did not meet its primary end points of less frequent and less intense trauma-related nightmares, greater improvement in sleep quality, and overall clinical status among veterans assigned to prazosin, compared with veterans assigned to placebo. While disappointing, and surprising given the results of the preceding studies, do these results predict a similar failure in the use of prazosin for treatment of posttraumatic headache?

In an observational study of 126 veterans with blast-related mild TBI during Operation Iraqi Freedom or Operation Enduring Freedom, 82% of participants had co-occurring conditions, including frequent, severe headache, neurologic exam abnormalities, or cognitive disorders. This pilot study found that treatment with prazosin and sleep hygiene counseling improved sleep, but also decreased headache pain and frequency, as well as improved cognitive function over nine weeks. Improvements were maintained for six months. Though difficult to determine the interplay of sleep, posttraumatic headache, and depression, could prazosin independently reduce the burden of headache? Currently, a double-blind, randomized, controlled trial in veterans is examining the effectiveness of prazosin as a preventive agent in treating combat-related posttraumatic headache. This study was scheduled to enroll its last patient at the end of 2017, and results may be out soon.

There may be specific pharmacologic properties that make prazosin a useful drug for headache treatment. Prazosin is a very potent, selective alpha 1-adrenergic antagonist that passes through the blood–brain barrier. It is highly protein bound (97%), so absolute amounts in the CNS are likely to be low. Its use in the treatment of hypertension is based on decreased peripheral vascular resistance as a result of arteriolar and venous receptor blockade. It also can act in the CNS to decrease sympathetic outflow. While an effect on headache could be central, peripheral, or both, other drugs with alpha-adrenergic blocking effects have been used in the treatment of migraine for decades. The ergots, for example, were the first alpha-adrenergic agents to be discovered acting as partial agonists or antagonists at adrenergic, tryptaminergic, and dopaminergic receptors. The hydrogenated ergot alkaloids are among the most potent alpha-adrenergic blocking agents, but adverse effects prevent doses that can cause more than minimal blockade. Chlorpromazine and other dopamine (D2) receptor antagonists, which are highly effective in acute treatment of migraine, particularly with parenteral delivery, also produce significant alpha-adrenergic receptor blockade, while trazodone, amitriptyline, and the atypical antipsychotics, with various levels of alpha-adrenergic antagonism, have found some success in migraine prevention.