What’s new with NDPH?

I have spent a little time introducing and reviewing New Daily Persistent Headache (NDPH), and what a miserable headache it is. We know that traditional headache medications and treatments are not particularly useful in alleviating NDPH.  But there are some new initiatives available, some research initiatives and novel approaches to NDPH treatment which may bring some positive answers. I happen to be involved in a research project funded by the Migraine Research Foundation and also in a novel treatment approach to treating NDPH at our tertiary pediatric headache clinic.  So while it can be disheartening to care for kids with this diagnosis, it can also be hopeful, if you can identify something that might just help.

Because NDPH often appears after a viral illness, some researchers have posited that the headache is part of a post-inflammatory or autoimmune response. It is also a chronic pain entity, so treatments used for chronic pain might be useful (chronic regional pain syndrome (CRPS) or fibromyalgia). Treatment options now being considered are those that reduce inflammation in the body, such as low-dose naltrexone, anti-inflammatory diets, and short duration lidocaine infusion.

Here are some of the ideas that are being researched concerning NDPH:

Research initiative: Endogenous Modulation and Central Sensitization in New Daily Persistent Headache (NDPH) in Children, Boston Children’s Hospital, Pediatric Headache Program.  This project has started and recruitment is ongoing.  The aims of this research are:

• Psychophysical Characterization of NDPH: To define differences in altered modulatory systems using offset analgesia in well characterized NDPH pediatric patients in the symptomatic and recovered state.
• Treatment Effects in NDPH: To define the effects of low-dose naltrexone on offset analgesia.
• Genetic Markers of Disease Persistence: To define the potential of chronic pain-related gene markers in predicting disease persistence.
• Brain Markers of Disease Resilience: To evaluate genetic and brain markers of disease state.

The proposed work would be the first comprehensive, study of pediatric NDPH. If successful it will provide insights into altered modulatory systems in the disease and define for the first time potential insights into mechanisms underlying chronicity vs. response.

Research initiative: Analysis of Headache Chronification with Imaging, Deep Phenotyping, and Proteomics, Stanford University School of Medicine

The purpose of this study is to better understand disease processes and risk factors involved in onset of chronic daily headaches/Chronic Migraines. They hope to learn more about the basic pathophysiology and neuromodulation of NDPH to determine effective treatment strategies and prophylactic measures.

Participation in this research study includes online questionnaires, a blood sample, a lumbar puncture, and a magnetic resonance imaging (MRI) scan without contrast to measure brain activity. This study was started in 2014, will continue until 2020, for patients over the age of 18 years.

Research initiative: Plasma Calcitonin Gene-Related Peptide and Nerve Growth Factor levels in New Daily Persistent Headache and Chronic Migraine to identify potential biomarkers and therapeutics targets, Montefiore Headache Center, NYC.

This research is studying whether CGRP or NGF levels are elevated in the plasma of New Daily Persistent Headache patients compared to those with chronic migraine and normal controls. This study is ongoing, for patients over age 18 years.

Treatment: Botox for NDPH: Recent reports from the Cleveland Clinic and Case Western Reserve describe patients with new daily persistent headaches (NDPH) who were treated with Botox injections (standard Botox for chronic migraine protocol). The improvement was modest (30%), with some reduction in headache pain, headache-free days not previously experienced, and positive effects lasting for 8 weeks. Available for patients over 18 years, and pending insurance approval (not FDA approved for this indication).

Treatment: Low dose naltrexone: Naltrexone is an anti-inflammatory agent, similar to the opioid antagonist naloxone, and an effective treatment for opioid addiction. It was recently discovered that when taken in low doses (1/10 of the typical dose), it may reduce the severity of chronic pain symptoms, by acting on the glial cells and other receptors in the nervous system. Because of its analgesic property, low-dose naltrexone may be an effective treatment for the management of several chronic pain conditions, including fibromyalgia and chronic headache. More research needs to be done to evaluate long-term effects of using low-dose naltrexone, and to assess the efficacy and safety of this medication in the treatment of patients with NDPH. If prescribed, this medication has to be prepared at a compounding pharmacy; retail pharmacies carry the standard 50mg tabs, and low-dose naltrexone is dosed at 4.5mg, which requires compounding, usually not covered by insurance.

Treatment: Short-duration lidocaine infusion: Lidocaine has been used as anesthesia and analgesia for more than 50 years, and is very effective at relieving nerve pain, chronic pain syndromes, and pain after surgery.  Lidocaine is an amide local anesthetic agent, which blocks fast voltage-gated sodium channels in the cell membrane of postsynaptic neurons, preventing depolarization and inhibiting the generation and propagation of nerve impulses.  Basically, lidocaine stops pain impulses from going to and from the brain, so pain is blocked.

In my pediatric headache program, we now offer short duration lidocaine infusions to our patients with New Daily Persistent Headache, the first program doing this with pediatric patients. It has been used in adult pain programs for chronic pain for many years. We hoped it would be effective for teens with NDPH, also a chronic pain condition, providing a decrease in pain level and/or reduction in the associated symptoms for these patients.

The protocol for short duration lidocaine infusion for patients over 50kg is 200mg of lidocaine IV over 2 hours , with appropriate monitoring for alterations in cardiac status and signs of lidocaine toxicity. For patients less than 50kg, 4mg/kg is given. At first, we did a bolus dose of 100mg over 30 minutes, followed by an infusion of the remaining 100mg over 1 hour.  Unfortunately, in the 1^st 3 months, almost all of the kids had side effects during the bolus.  So we changed to a 2 hour infusion which has been much better tolerated, many fewer reactions.

So what are the results? Well at first we were disappointed because there was really minimal reduction in headache pain. Then, it became clear that the benefits were more significant in reducing the other symptoms. In particular, patients were achieving improvement in their persistent nausea, dizziness, difficulty with concentration, difficulty with physical activity, mental clouding, fatigue and overall functioning. And for the majority of patients who responded positively, they did not return all the way to baseline after several months, with sustained improvement.  We have a number of patients who come in every 3 months and repeat the infusion because it has benefitted them so much.  What the kids tell me is that they can actually tolerate the headache pain, when the other symptoms are reduced, but have a great deal of trouble functioning with both headache and the rest of their symptoms. I think the kids who have many associated symptoms seem to get the most benefit and improvement.  I will put a copy of the poster abstract we did about this- preliminary results over the first year- in resources.

This is an initiative I am quite involved with, screening, monitoring during infusion and follow up with data collection. It is exciting to find something that is showing benefit to my kids with NDPH. Granted, we only have about 60% positive response rate, but for those 60%, it is wonderful.

We will be continuing this initiative and collecting data and at some point be putting together an academic paper to share. I am also hopeful that some of the research work will also yield positive results. At the very least a better understanding of the pathophysiology of NDPH would help guide future therapies.

I will discuss more about NDPH trajectory for resolution and other matters in the next post.