The inaugural Professor James Lance AO CBE Award
Making headway into migraine: assessment of subcutaneous lignocaine and ketamine use in the management of chronic (transformed) migraine and development of a biomarker of headache.
Migraine is the most prevalent disabling neurological disorder and has a major impact on health resources. Prevalence of migraine is more common than asthma and diabetes combined, affecting 16% of the population (18% of women and 6% of men) . In the Global Burden of Disease Survey of 2010, migraine ranked as the 3rd most prevalent disorder and 7th highest specific cause of disability worldwide. Migraine carries a significant economic burden of disease, incorporating loss of productivity and work absenteeism, long term need for medications and recurrent visits to health professionals.
There are several different theories as to what causes migraine. To name a few, spasm of blood vessels is often implicated; or activity of different neurotransmitters, or abnormal electrical activity of pain nerves. Reflecting this, medications used for treatment of migraine differ in their mechanisms of action: there is no ‘one drug suits all’. While there have been major advances in understanding physiology of migraine in recent decades, there is no consensus on the assessment of the condition and no clinical tool to serve as a biomarker of disease or treatment response. The burden of disease is amplified in patients with transformed or chronic migraine, which represents 7.7% of the total migraine population. Patients who experience suboptimal headache control may overuse shortacting analgesics (especially codeine and tryptans), and are at risk of an additional component of analgesic rebound headache which may perpetuate migraine. This study focuses on patients with chronic migraine. It seeks to obtain pilot data for use of subcutaneous lignocaine and ketamine infusion in treatment of transformed (chronic) migraine in use at St Vincent’s Private Hospital and to evaluate nerve excitability studies as an in vivo biomarker of migraine pathophysiology and treatment response.
In work leading up to this project, Dr Susan Tomlinson has (with the support of Brain Foundation Research Gifts) established proof-of-principle that nerve excitability studies can be used to detect changes in peripheral nerve excitability in patients with neurological conditions affecting the central and peripheral nervous system or both (see Chief Investogtors publications 1,3, 7,9, 10). Studies to date have largely involved patients with single-gene ion channel disorders including epilepsy and ataxia. This has laid the ground work to apply the principles to more common conditions in which the cause is not known; specifically, neuropathic pain and idiopathic epilepsy; and studies are due to complete in 2017. As a result of current projects, it has emerged that application of nerve excitability studies to migraine is highly relavent, as the genetic models of migraine pertain to single-gene ion channel disorders and many medications used to treat migraine modulate ion channel function. Futhermore, A/Prof Raymond Garrick has developed a protocol to treat patients with chronic migraine which appears to be highly effective and anecdotally is transformative in the lives of this cohort of patients. The collaboration of the coinvestigators would enable us to obtain objective evidence for a new treatment to a very challenging problem.
We hypothesise that patients with transformed migraine/chronic daily headache have complex physiology. The chronicity of the headache is perpetuated by sensitized, neutrally driven pathways. Inpatient management with a prolonged (approx. 10 day) subcutaneous infusion of lignocaine and ketamine may provide adequate analgesia and stabilization of these entrenched pathways to break the cycle of pain, enable withdrawal of medications that perpetuate headache (e.g. codeine and triptans) and allow introduction of preventative agents.
We hypothesise that nerve excitability studies will be able to detect changes in peripheral nerve in patients while they receive the infusion and may also document differences in nerve excitability before and after treatment, thus potentially proving a useful biomarker of disease and treatment response.
Aim 1: .To evaluate the effectiveness of continuous (7-10 days) subcutaneous lignocaine and ketamine infusion protocol for treatment of transformed (chronic) migraine with regards to frequency and severity of migraine, lost days of productivity and amount of headache medication required.
Aim 2: To obtain peripheral nerve excitability studies in patients with transformed (chronic) migraine before, during and after treatment with lignocaine/ketamine infusion in order to develop an in vivo biophysical marker of change in these patients with treatment, as well as an objective measurement of lignocaine effect during infusion.