Medication Overuse Headache

New evidence suggests that opioid overuse headache may involve activation of glial cells, in particular astrocytes and microglia, which creates a pro-inflammatory state that leads to pain facilitation.

By Q&A WITH JACINTA JOHNSON, B.Pharm
 

“You do it to yourself, you do/
And that›s what really hurts, is
You do it to yourself, just you”

It’s perhaps a fool’s errand to try to decipher meaning in the unceasingly cryptic lyrics of Radiohead front man Thom Yorke, but it’s reasonable to assume the band’s 1995 hit, “Just (You Do It To Yourself),” wasn’t an attempt to dispense medical advice for medication overuse headache (MOH). But the sentiment is the same: Patients who develop MOH are unwittingly administering and exacerbating their own pain and suffering.

MOH is a chronic daily headache in which acute medications used at high frequency cause a transformation to headaches occurring 15 or more days per month for four or more hours per day if left untreated.1 The prevalence of MOH is one to two percent in the general population worldwide, and because of the tremendous socio-economic cost, one recent study said it is likely to be the most costly neurological disorder.2

Here, Jacinta Johnson, B.Pharm (Honors) and a PhD candidate at the University of Adelaide, in Southern Australia, discusses MOH and her team’s recent study on MOH and opioid-induced hyperalgesia.

WHAT FACTORS ARE ASSOCIATED WITH ACUTE MEDICATION OVERUSE HEADACHE?

Clinically, the presentation acute medication overuse headache depends on a number of factors, such as the type of primary headache the patient originally suffered from and which type of medication they are overusing. Medication overuse headache in patients with primary tension-type headache tends to be dull and have pressing or tightening characteristics, whereas patients with primary migraine overusing triptans often report an increased frequency of migraine-like headaches. Interestingly, patients who begin with migraine and overuse analgesics rather than triptans often develop a daily or near-daily tension-type headache and continue to experience superimposed migraines.

A range of other factors has also been associated with medication overuse headache, including depression, anxiety and dependence/substance abuse disorders, which can complicate treatment further.

WHAT ARE THE TREATMENT OPTIONS? COMPLEMENTARY AND ALTERNATIVE MEDICINES ARE POPULAR FOR MOH. DOES THE LITERATURE SUPPORT ANY OF THESE?

At present the primary treatment for medication overuse headache is simply to withdraw the overused medication. However, as you would imagine this is much easier said than done. Acutely, medication withdrawal is often very difficult and distressing for patients, as the headache tends to get worse before it gets better. In complex or resistant cases patients can be admitted to hospital to facilitate this withdrawal, yet for patients with work or family commitments a week or so in hospital may not feasible.

There is now some evidence indicating topiramate and botulinum toxin A may actually be able to reduce the headache burden prior to medication withdrawal, which has launched a debate about when prophylactic therapies should be initiated. Some doctors believe preventative treatments should be started prior to withdrawal, to help ease patients through, while others prefer to wait until medications have been withdrawn. As a significant percentage of patients will improve without any preventative treatment, thus starting prophylactic therapy too early could expose additional patients to treatment adverse effects unnecessarily. At the University of Adelaide we are conducting a clinical trial of a glial-targeted treatment called ibudilast in opioid overuse headache, which we hope will reduce headache pain and also make it easier for patients to get through the opioid withdrawal period, as it has been found pre-clinically to reduce pain and clinically to reduce withdrawal symptoms in opioid addicts.

Scientific support for complimentary medicines in the treatment for medication overuse headache is scarce, however this does not mean such therapies are not useful for some patients. Acupuncture has been reported to reduce the frequency and intensity of chronic headaches in general, and massage and meditation can help to reduce stress and pain, therefore these alternative treatments may be worth trial in patients with medication overuse headache, especially when other treatments have been in effective or poorly tolerated. There is some evidence for the use of the herb feverfew and magnesium supplements in preventing and reducing they severity of migraines, however to my knowledge studies specifically in medication overuse headache have not been conducted.

HOW FREQUENTLY REBOUND HEADACHES OCCUR DEPENDS ON THE TYPE AND DOSE OF OVERUSED DRUG AND THE FREQUENCY OF HEADACHES. WHAT ARE THE DIFFERENCES BETWEEN THE DRUGS/DOSE?

There are still a lot of unknowns with regard to which drugs are capable of inducing medication overuse headache in what doses. From the literature it is clear opioids are a particularly problematic class of medications, as they have consistently been associated with progression from episodic to chronic headache, even when initiated for other indications. Use of barbiturates has also come out as a significant risk factor in headache chronification in a large longitudinal study. Overall, non-steroidal anti-inflammatory drugs (NSAIDs) are not associated with transition from episodic to chronic headache, in fact in patients who begin with headaches around up to 9 days per month NSAIDs are protective against chronic headache, however in patients with very frequent headaches at baseline NSAIDs can the increase risk of chronic headache. Although many studies report an improvement in headache when overused triptans are withdrawn, prospectively triptans have not been shown to increase the risk of chronic headache.

The specific doses that can lead to medication overuse headache, and conversely those that are safe to consume, are not well established. Often in medication overuse headache studies drug dose in defined in terms of days of intake per month, rather than amount of the drug consumed, thus it may be that the frequency of intake rather than the absolute dose is more important in determining outcome. It has been reported that the critical intake for opioids is around 8 days per month, which conflicts somewhat with the arbitrary cut-off of 10 days per month of intake required for an official ICHD-II diagnosis of opioid overuse headache.

WHAT SHOULD NEUROLOGISTS TAKE AWAY FROM YOUR STUDY?

Our paper (Cephalalgia; 33(1):52-64) puts forward a hypothesis as to why patients with primary headache disorder may progress to develop medication overuse headache following opioid intake, where as other patients, taking the exact same medications, in exactly the same doses for the same periods of time, do not. We believe opioid overuse headache may involve activation of glial cells, in particular astrocytes and microglia, which creates a pro-inflammatory state that leads to pain facilitation. This tendency towards pain facilitation may mean that previously sub-threshold triggers are now more likely to induce headache, and it could be that headache patients, but not other patients, are particularly susceptible to the glial-activation caused by opioids as their glial cells have been ‘primed’ to over-respond by previous headaches.

Thus, treatment strategies aimed at attenuating glial activation may be of benefit alongside medication withdrawal in patients with opioid overuse headache - and we are evaluating one such exciting treatment, ibudilast, in a clinical trial in Adelaide (Australia) at the moment.

  1. Tepper SJ. Medication-overuse headache. Continuum (Minneap Minn). 2012 Aug;18(4):807-22.
  2. Russell MB, Lundqvist C. Prevention and management of medication overuse headache. Curr Opin Neurol. 2012 Jun;25(3):290-5.
 

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