Abstract
Chronic headache, defined by the presence of headache on at least 15 days per month (1), is a widespread problem affecting approximately 4% of adults (2). Epidemiology studies demonstrate that medication overuse plays a role in a quarter to a third of these cases (3,4), indicating that it is a substantial contributor to the burden of chronic headache. Medication overuse headache (MOH) is identified by the transformation of an episodic headache pattern to chronic headache while a person is taking an acute analgesic for headache on at least 10–15 days per month (1). Essentially any acute medication for headache can be associated with MOH in individuals with an underlying primary headache disorder such as migraine or tension type (5,6).
Evidenced by the fact that the United States economy loses US$13 billion per year from the lost 113 million workdays due to headache, managing chronic headache, a condition associated with significant disability and broad societal impact, is an important endeavor (7). As there are no clear guidelines on treating the medication overuse component of this problem, but complete discontinuation of the overused medication remains a vital part of the treatment plan, detoxification strategies can be varied and include inpatient and outpatient methods (8–10). When the offending medication is stopped, however, the headache tends to worsen before it improves and, depending on the medication, patients may also experience other withdrawal symptoms such as nausea, anxiety, sleep problems, agitation, tachycardia, and blood pressure changes. Often, to mitigate the withdrawal headache, patients are given a short course of steroids (11). Although information gathered from the effects steroids and neurosteroids have on neuronal activity (reducing neurogenic inflammation, decreasing vasogenic edema, and acting on central aminergic and serotonergic pathways) (12) suggests that they can be beneficial in reducing withdrawal headache, until now there have been no large-scale high-quality clinical trials on this topic and the few small studies have yielded mixed results (13>–15).
In this issue of Cephalalgia, Rabe et al. (16) present a prospective, multicenter, randomized, double-blinded, placebo-controlled study evaluating the role of prednisone in managing withdrawal headache in patients with chronic headache occurring as a result of an underlying headache diagnosis of migraine or tension type, complicated by MOH. Ninety-six subjects were enrolled and equally divided into treatment and placebo groups. The subjects received either prednisone 100 mg or placebo for 5 days and were monitored for a number of hours with moderate or severe headache for the first 3 days of withdrawal. Secondary end points included number of moderate or severe headaches during the first 5 and 14 days of withdrawal, and the amount of acute analgesics used during each time frame. Interestingly, although there was no difference between the two groups with regards to the number of hours of moderate or severe headache during the first 3, 5, or 14 days of withdrawal, those in the prednisone group opted to use fewer acute analgesics during the first 3 days (p = 0.021, 1.1 versus 2.3 doses). However, this difference in medication intake was no longer present by days 5 and 14. As expected, patients who had been overusing triptans had a shorter and less complicated withdrawal period, whereas those overusing combination analgesics had a more difficult and protracted withdrawal; however, these differences stemming from the class of overused analgesic were not significant.
This study is the first large, randomized, prospective, double-blinded, placebo-controlled study investigating the utility of a short course of steroids in treating MOH. Although no difference was seen between the treatment and placebo groups in terms of headache intensity, it is noteworthy that at least for the first 3 days of withdrawal, the treatment group required fewer analgesics regardless of the underlying primary headache type or class of medication being withdrawn. The mechanism behind this finding is unclear and the authors offer a few hypotheses for this positive result. From a clinical standpoint, this study offers useful information to be considered when making medication decisions during MOH treatment. Although a short course of steroids may not lead to a shorter withdrawal period and milder withdrawal headache, some patients may benefit from their administration as steroid use can lead to a reduced need for other analgesic intake. Particularly in patients who are overusing acute analgesics, this benefit may be important.
The authors of the study provide some limitations to the study including a high drop-out rate, lack of headache data prior to the withdrawal period, patient information regarding MOH-years and the long term outcome beyond the 14-day period.
Although rescue medication consumption was statistically significant between the two groups, it is unclear if the type and dose of the rescue medications were the same as or similar to their overused medications and if this consumption was different between the two groups independent of the frequency. In addition, it would be helpful to know if the patients had any insight into which treatment they received and whether their awareness was different between the prednisone versus placebo groups.
In the study design, although there was mention that prophylactic medications could be started during withdrawal, it is unclear if any prophylactic agent was started or underwent dose adjustment during the study. This factor needs to be considered when comparing the two groups as prophylactic medications such as topiramate (17) have been shown to be effective in MOH.
As documentation of the headache occurred only during wakefulness, it would be interesting to see if the wakeful period was different between the two groups as the hours of headache would differ. This would be relevant when considering the effect of prednisone on sleep.
Although the study was not designed to look for this factor, the authors did not find a difference in outcome between the inpatient and outpatient populations. This finding has been ascertained by Creac’h et al. (18) and is important when taking into account the costs associated with inpatient admissions.
Future studies may include comparing pre-withdrawal headache severity to post-withdrawal headache severity between prednisone and placebo groups, dose response differences in steroids and effects of delayed steroid use after withdrawal from medication overuse intake (i.e. starting steroids 5 days after withdrawal from medication overuse). In addition, subsequent trials could examine patient and medication factors that could contribute to outcome, such as continuous daily headache versus intermittent chronic headache, the type, dose, and duration of medication overuse, and the type and dose of rescue medications during the study. Finally, the long-term success rate of implementing this therapy needs to be considered in terms of both headache severity and duration and medication use beyond 14 days. Future studies should also look at the long-term changes in these factors when comparing prednisone verses placebo.