Australasian Science Magazine

Regular use of the painkiller codeine can actually increase sensitivity to pain.

By James Swift, Jacinta Johnson & Paul Rolan

Chronic headache is poorly understood and notoriously difficult to manage, but immune-targeted medications and electrical stimulation could provide fresh insight into the root cause and treatment of this debilitating condition.

Picture this scenario: you’ve had a hectic afternoon, you haven’t had time to eat since breakfast and your head feels like it’s trapped in a vice that slowly tightens its grip as time passes by. Does this sound familiar? If so, you are one of the many who have suffered with a headache classified as a tension-type headache.

Or perhaps a throbbing pain is engulfing one side of your head, the light and sound in the room feels like it’s amplifying the pain, and you start to feel a rising sense of nausea? These symptoms are typical of another type of headache known as migraine. And while tension-type and migraine account for the vast majority of all headaches, there are many other presentations of this condition too.

Anyone can experience a headache in one form or another. More than 90% of people do at some point during their lifetime, but what can be done about it? For most of us relief can be sought through simple means such as a breath of fresh air, a glass of water, a lie down or a dose or two of simple painkiller medication.

However, headaches are not merely an occasional hindrance for 2–3% of the community. Some people experience headache on a daily or near-daily basis, a condition referred to as “chronic headache”. Increased frequency isn’t the only hallmark of this condition; it also carries with it increased severity of pain and can be associated with chronic fatigue, depression, anxiety, sleep disturbances and disrupted memory and concentration.

Simple remedies, like those listed above, have little or no impact on chronic headache, and prescription-only treatments are limited and often associated with undesirable side-effects. All too often patients then resort to taking very large quantities or combinations of these medications in a desperate attempt to obtain some relief; this in itself presents significant problems. At a fundamental level, headache treatments are also inadequate as they are mostly symptomatic in their action, dampening pain signals rather than targeting the pathology that might underpin headache.

It is fairly easy to see how chronic headache carries with it a huge burden that greatly affects an individual’s quality of life. Emotional well-being, relationships, employment, general health – very little is left untouched. In turn, this has a massive societal impact, with migraine alone estimated to cost Australia hundreds of millions of dollars per annum.

Given the nature of the condition and the lack of appropriate therapies, chronic headache can be a heavy burden on sufferers. Coupled with its relatively high prevalence in society, chronic headache represents a major unmet medical need. This has led us to investigate a range of innovative treatments for chronic headache conditions.

Traditionally, headache research has been conducted by neurologists who focused primarily on the blood vessels and nerve cells in the brain. Recently, advances in other areas of pain research have shed light on the role of the immune system in modulating pain.

In a world-first, we have recently confirmed that regular use of the painkiller codeine can actually increase sensitivity to pain. Further laboratory studies indicated that an overactive immune system may be involved. We suspect that regular codeine use increases pain by activating immune cells in the nervous system, causing them to release substances that create inflammation around the nerve cells.

Based on this hypothesis we tested a drug called ibudilast, which is not on the market in Australia, to calm down over-active immune cells in the nervous system in an animal model. We found that ibudilast reversed codeine-enhanced pain sensitivity, and are now conducting clinical trials to test this immune-targeted medication in patients with chronic headaches. Specifically, we are running trials to look at how effective ibudilast can be in the treatment of chronic migraine and a lesser-known condition called “medication overuse headache” in which headache is exacerbated by frequent use of painkillers.

Medication Overuse Headache

Over the past few decades it has become apparent that the frequent use of painkillers, which are quite effective for headache in the short-term, may actually make headaches worse in the long-term. A vicious cycle can develop where the patient takes painkillers, which make the headaches worse so more painkillers are taken, worsening the headaches further.

What is particularly mind-boggling about medication overuse headache is that it can also develop in patients with occasional migraines or tension-type headaches when they start taking painkillers on a regular basis for another condition, such as back pain or arthritis. However, if a patient with arthritis and no history of headaches takes the exact same painkillers, in the exact same doses, for the exact same period of time, they do not develop medication overuse headache.

This tells us that there is something different about patients who suffer occasional headaches that makes them susceptible to the pain-worsening effects of painkillers. We think this difference may lie within the immune system.

At present, the main treatment for medication overuse headache is to simply withdraw the overused medication. Unfortunately, this can be quite difficult and distressing for patients, as the headache often gets worse during withdrawal before it gets better. Consultation with a headache specialist is often required, and in some cases patients are even admitted to hospital while they withdraw from their painkillers.

Furthermore, most medications currently used to prevent headaches cause troublesome side-effects, such as drowsiness and slowed ability to think, because they work on nerve cells. The medication we are trialling is different because it targets the immune cells and is free from a lot of the side-effects that complicate treatment with other headache preventative drugs.

In our first study, patients with medication overuse headache who took codeine or similar painkillers on at least 10 days per month and suffered headaches on at least 15 days each month were randomised to receive ibudilast or inactive placebo capsules twice daily for 8 weeks. Patients recorded their headaches in a specialised headache diary for a month before starting on the study medication and throughout the treatment period. These diaries will be reviewed at the end of the study to determine if ibudilast was able to reduce the number of headaches suffered.

Migraine

The first clue that migraine may involve abnormalities in the immune system came from the observation that allergic conditions such as asthma, eczema and hayfever occur more often in patients with migraine. Studies have since found a clear relationship between migraine pain and a range of inflammatory substances released by immune cells. Thus, we hypothesise that chronic migraine, like medication overuse headache, may also be mediated by the immune cells in the nervous system.

Therefore, in a second study, we are trialling ibudilast in patients who suffer from chronic migraine but do not overuse painkillers. These patients have a headache at least 15 days per month, and most of those headaches have migraine qualities such as throbbing pain on one side and additional symptoms such as nausea and sensitivity to light or sound.

In this study, patients receive ibudilast or inactive capsules twice a day for 8 weeks, and then swap to receive the alternative treatment for a further 8 weeks. As in our first study, patients will record their headaches in diaries that will be evaluated to ascertain treatment effectiveness.

Chronic Tension-Type Headache

Immune-targeted medications are not the only new headache management strategies on the horizon. We are also investigating a device to see if it is useful in treating patients with chronic tension-type headache.

This disorder is characterised by a dull, constant feeling of pressure or tightening that affects both sides of the head with a frequency of 15 or more days with headache per month. It was previously thought that contraction and stress of muscles in the head and neck were the cause of this condition, hence its original title: tension headache. Given the pain experienced with this condition, it seemed a very plausible explanation. However, detailed research of the muscles in these regions has revealed that no such abnormalities occur in people suffering with this condition, so tension-type headache is now the official term.

Many ideas have since been proposed to explain the pathology of chronic tension-type headache. The best-supported explanation is that pain-processing regions of the brain can become overly sensitised and trigger the painful headache episodes.

Precisely what leads to the development of this sensitisation remains to be revealed, but a variety of clinical studies investigating the overall pain experience of people suffering with chronic tension-type headache has provided substantial evidence backing this theory. This, in turn, has expanded the way in which doctors and scientists think about the treatment of conditions like chronic tension-type headache – can the overly sensitive pain centres in the brain be dampened down or reset?

To this end, the treatment we are investigating is called transcranial direct current stimulation (tDCS), which is a well-tolerated, non-invasive and relatively inexpensive method of stimulating (but not activating) the outer regions of the brain using low power direct current. This is a particularly attractive option for the treatment of chronic headache because it is a completely drug-free approach and may therefore help individuals avoid the pitfalls associated with large amounts of medication.

To apply tDCS, two damp, sponge-like pads (i.e. an anode and a cathode) are placed on specific parts of the scalp and held in place with a rubber strap. The pads are connected to a battery-powered machine that can generate a direct current at low power. When activated, the current passes between the pads via the underlying region of the brain. Nearly all participants in tDCS studies report nothing more than a mild tingling sensation on the scalp under one or both of the pads when the device is activated. This form of electrical stimulation has been previously studied in a variety of chronic pain conditions as well as stroke, depression and epilepsy, with promising results reported.

For our study, tDCS will be used to target the brain’s motor cortex , which is responsible for movement. At first glance, this may seem like an unusual way to treat pain. Why target the outer-lying movement control centre of the brain in order to treat the pain-processing regions deep within the brain?

Although the answer to this is not yet fully understood, many previous studies investigating stimulation of the motor cortex, from non-invasive through to highly invasive surgical methods, have shown a significant reduction in pain in a wide variety of conditions. This is likely because there are countless interconnections between the outer regions and deeper regions of the brain.

This weight of evidence can’t be overlooked. Our study will investigate whether ten 20-minute sessions of tDCS treatment is effective in reducing the severity, duration and frequency of headache episodes in chronic tension-type headache.

The studies highlighted here are still in progress, so reporting on the results is not yet possible. Irrespective of the outcome, our approach represents an exciting frontier in chronic headache research – a shift away from the less-specific, symptomatic medications of old towards disease-modifying, targeted treatments of the future.

We are not the only scientists engaged in this pursuit. Other groups around the world are applying similarly innovative ideas to the treatment of headache too.

Combined with increasing awareness and understanding of headache by society at large, the day is drawing nearer when headache treatment will be just as easy, yet far more effective than “a cup of tea, a Bex and a good lie down”.

Paul Rolan is a headache and chronic pain specialist who supervises PhD candidates James Swift and Jacinta Johnson at the University of Adelaide’s School of Medical Sciences.