Background
Medication overuse headache (MOH) is considered to be an important problem among headache patients worldwide with an estimated prevalence of 1–1.5% in the general population [
1‐
5]. Studies mainly performed in tertiary care headache centers found that migraineurs and, to a lesser extent, patients with tension type headache are at risk for worsening of their headache under regular intake of acute relief medication [
6]. Although MOH is prevalent in patients of all age groups, a considerable part of the working population is affected. MOH therefore might have an important socioeconomical impact.
MOH is a concept based on clinical observations first described in the late 1950s [
7]. The underlying mechanisms are still unclear [
8]. Recent findings suggest that the regular intake of an analgesic substance might lead to changes in different neurobiochemical systems; e.g. the serotoninergic system is modulated by the intake of different classes of analgesics which will lead to alterations of the antinociceptive serotoninergic pathway and central sensitization [
9‐
16]. Other mechanisms proposed involve the NMDA-receptor [
17], the opioid- system [
18], and alterations in membrane transduction [
19].
New diagnostic criteria vor MOH were introduced in 2006 [
20] (see Table
1 for diagnostic criteria). Population-based studies have identified possible risk factors for the development of chronic headache, such as age, female gender, low socioeconomic status, non-married civil status, obesity, snoring, comorbid musculosceletal pain, head and neck injury, and stressful life events [
21,
22]. This has raised the question whether chronic headache is the consequence or the cause of overused analgesics [
21,
23]. The development of “de novo” MOH in patients overusing analgesics would establish this causative relationship, however, prospective studies on that topic are missing. Patients taking analgesics for chronic pain - other than headache - represent an interesting population to examine such a context. Previous studies, using other than the ICHD-II-Appendix criteria for the definition of MOH, showed conflicting results regarding new onset headache under medication overuse [
24‐
28].
Table 1
Overview of the different criteria for Medication overuse headache (MOH)
Comment | not defined | Different entities for different substances | Elimination of headache characteristics | Elimination of criterion D |
A
| | Headache1 > 15 days/month | Headache ≥ 15 days/month | Headache ≥ 15 days/month |
B
| | Substance overuse ≥ 10/152 days/month | Substance overuse ≥ 10/152 days/month | Substance overuse ≥ 10/152 days/month |
| | for ≥ 3 months | for > 3 months | for > 3 months |
C
| | Headache developed or worsened | Headache developed or worsened | Headache developed or worsened |
D
| | Resolution within 2 months after withdrawal | Resolution within 2 months after withdrawal | n.a. |
The objective of the present study was to examine the prevalence of MOH as defined in the new ICHD-II-Appendix criteria in a population of patients with chronic pain different than headache. Our hypothesis was that chronic headache would be more prevalent in patients with analgesic overuse (AO), especially when additionaly suffering from primary headaches, such as migraine or tension type headache.
Methods
The interdisciplinary pain clinic at the University Hospital of Zurich is a tertiary referral center for chronic pain patients. Participating specialists are an anesthesiologist, a neurologist, a psychiatrist and a rheumatologist. Patients were referred directly by General Practitioners and Specialists from the whole region of Zurich without selection bias from any of the participating specialists. Upon referral, every patient is examined by each specialist separately in the course of one week. The examination consists of a careful and pain-specific history taking and a physical examination. Headache diagnosis of all affected patients are made by a well trained neurologist (PS) according to ICHD-II and ICHD-II-Appendix criteria regarding MOH, respectively [
20,
29]. At the end of the week patients are dicussed in a meeting to elaborate a comprehensive diagnostic worksheet and to provide a treatment plan, based on clinical findings and pathophysiological considerations. After informing the patient about the results, a comprehensive report is written to the referring general practicioner or specialist.
The study was approved by the local ethical committee and conducted according to the principles of the Declaration of Helsinki. All patients had signed an informed consent to allow subequent use of their data for study purposes. For the study period (September 2005 to December 2007) data were collected from the comprehensive reports retrospectively. If necessary, additional demographic data, information about pain symptoms, pain scores, mood disturbances and drug intake, or specialists’ examination protocols was taken from the patients charts.
Data collection
Data of all patients referred to the interdisciplinary pain clinic were screened. Exclusion criteria were: headache as the sole pain symptom; incomplete examination (defined as examination by less than 3 specialists) and missing data on medication intake. The information collected for this study included demographic data regarding age; gender; history of migration (defined as having a mother tongue other than one of the four Swiss national languages: Swiss-German, French, Italian, Rumantsch); duration (years) of pain suffering; history of head and/or neck trauma, and use and type of acute medication. The disorders were categorized into: “neurologic”, “rheumatologic”, “psychiatric” and “other”. Headache diagnosis and comorbidity of “depression” and “anxiety” were additionally recorded.
For comparative analysis, patients were categorized in two subgroups “analgesic overuse (AO)” and “no analgesic overuse (noAO)”, in analogy to the criteria for medication overuse headache (MOH) defined by the ICHD-II Appendix (10 or more days for triptans and opioids, 15 or more days for analgesics). Age, gender, years of pain suffering, history of migration, history of headache, history of accident (subsequently refered to as “accident”), depression and anxiety were defined as possible associated factors for analgesic overuse.
Statistical analysis
For the analysis of the primary hypotheses, Fisher’s exact test comparing binary variables was performed. For the univariate analysis of associations the Fisher-Test was applied for binary and nominable variables. For continous variables, a t-test was performed for normally distributed and a Mann–Whitney-U-Test for not normally distributed data. For all significant factors, OR with 95%-confidence interval was provided. A significance level of p < 0.05 was defined. For multiple testing Bonferroni-corrected p-values were used. Regarding associations for medication overuse, a multiple logistic regression was performed with all factors significant at univariate analysis, and OR with 95%- confidence interval provided.
Discussion
So far, five studies on MOH in chronic pain patients have been published [
24‐
28]. Lance et al. found that 24 of 89 patients in a rheumatology clinic had headache on 4 to 28 days per month while taking more than 14 tablets per week; no significant difference in headache frequency between those taking more or less than 14 tablets per week was found [
26]. Bowdler et al. reported 6 patients complaining of chronic headache out of 1411 consecutive cases (0.4%) in an anesthesiological pain clinic, of which 140 (9.9%) had regular non-opioid analgesic intake [
25]. In 28 patients taking opioids regularly for bowel motility control after total colectomy, Wilkinson et al. found 8 patients with daily intake of opioids; while two of them suffered from chronic daily headache and both reported a history of previous migraine [
27]. Bahra studied a population of 111 patients in a rheumatology clinic, identifying 103 patients with regular analgesic use; of those, 8 (7.6%), all migraineurs, suffered from CDH [
24]. Finally, another population from a rheumatolgy clinic was studied by Williams et al., finding that 14 of 114 (12%) patients suffered from chronic daily headache, whereas 9 (8%) patients met the criteria for problable MOH according to ICHD-II revised criteria [
28,
30]. However, all those studies have been using diagnostic criteria other than current ICHD-II-Appendix definition for MOH, and therefore comparison with our data is difficult.
The prevalence of 29% for MOH in our pain population is higher than previously reported. Different reasons may explain our finding. First, ICHD-II-Appendix criteria enable more patients to be diagnosed with MOH at the time of the examination. The rationale behind this is to increase awareness for the problem and to allow more patients to benefit from specific treatment [
20]. Reports of underestimation of MOH in clinical practice support these arguments [
3,
24]. Due to the retrospective nature of our study, the prevalence of MOH might have been overestimated because of incomplete information on the timing of headache chronification and beginning of medication overuse (criterion C of the definition, [
20]). Also, our population consisted of patients referred to a tertiary pain clinic because of long-standing and complex pain problems, as reflected by the high number of cummulative diagnostic categories in the majority of cases. In Switzerland, healthcare system allows free access to specialists for most people. Patients may consult more than one specialist for their complex health problem, leading to prescription of analgesics by different doctors without knowledge of the patients current drug treatment. Many of the analgesics taken are even over the counter (OTC), what represents another risk factor for uncontrolled analgesic intake. Due to the retrospective nature of our study we have to take into account methodological limitations. These limitations apply to adequacy and bias of data collection due to quality of recorded information and inadequacy of patient’s reports, as already mentioned. However, more inclusive criteria would produce more false positive cases, i.e. patients with headache chronification unrelated to medication overuse, will be diagnosed with MOH [
31]. Hence, some researchers have challenged the hypothesis of medication overuse leading to chronic hedache. They criticized that the primary clinical observation for the concept of MOH, i.e. improvement of headache after discontinuation of medication overuse, has never been demonstrated in a placebo-controlled trial, and has yet to be formally proved [
32]. On the other hand, the fact that a subset of patients does improve in their headache pattern after withdrawal cannot be disregarded. The conclusion that we
can draw from this controversy is that in some headache patients the headache will chronify as a consequence of the medication overuse, while in others the chronification is caused by other factors.
Comorbid depression, history of migration, history of headache and have been identified as independently associated factors for analgesic overuse in general, this is in line with previous studies [
33‐
35]. The association of having a history of primary headaches among the MOH patients, is in line with other studies. This accounts especially for migraine. In contrast to Radat et al., we found no significant correlation between anxiety and medication overuse [
36]. However, psychiatric evaluation was not done using standardized questionnaires.
Competing interests
Possible conflicts of interest (including financial and other relationships) for each author include the following: CWS: no. KM: Received travel support for consulting or lecturing from the following companies: Pfizer AG, Zurich, Switzerland; Bristol-Myers Squibb SA, Baar, Switzerland; Mundipharma Medical Company, Basel, Switzerland; Janssen-Cilag AG, Baar, Switzerland; UCB, Bulle, Switzerland; Medtronic, Bern, Switzerland; Boston Scientific AG, Solothurn, Switzerland; B. Braun Medical AG, Sempach, Switzerland; Grünenthal Pharma Schweiz, Mitlödi; Switzerland; St. Jude Medical AG, Zurich, Switzerland. DMS: no. EA:Received honorarium and travel support for consulting or lecturing from the following companies: Grünenthal GmbH, Aachen, Germany and Mitlödi, Switzerland, Pfizer AG, Zürich, Switzerland. DRS: His academic department is receiving grant support from the Swiss National Science Foundation, Berne, Switzerland (grant numbers: 33CM30_124117 and 406440-131268), the Swiss Society of Anesthesiology and Reanimation (SGAR), Berne, Switzerland (no grant numbers are attributed), the Swiss Foundation for Anesthesia Research, Zurich, Switzerland (no grant numbers are attributed), Bundesprogramm Chancengleichheit, Berne, Switzerland (no grant numbers are attributed), CSL Behring, Berne, Switzerland (no grant numbers are attributed), Vifor SA, Villars-sur-Glâne, Switzerland (no grant numbers are attributed). DRS was the chairman of the ABC Faculty and is a member of the ABC Trauma Faculty which both are managed by Thomson Physicians World GmbH, Mannheim, Germany and sponsored by an unrestricted educational grant from Novo Nordisk A/S, Bagsvärd, Denmark and CSL Behring GmbH, Hattersheim am Main, Germany. In the past 5 years, DRS has received honoraria or travel support for consulting or lecturing from the following companies: Abbott AG, Baar, Switzerland, AMGEN GmbH, Munich, Germany, AstraZeneca AG, Zug, Switzerland, Bayer (Schweiz) AG, Zürich, Switzerland, Baxter S.p.A., Roma, Italy, B. Braun Melsungen AG, Melsungen, Germany, Boehringer Ingelheim (Schweiz) GmbH, Basel, Switzerland, Bristol-Myers-Squibb, Rueil-Malmaison Cedex, France and Baar, Switzerland, CSL Behring GmbH, Hattersheim am Main, Germany and Bern, Switzerland, Curacyte AG, Munich, Germany, Ethicon Biosurgery, Sommerville, New Jersey, USA, Fresenius SE, Bad Homburg v.d.H., Germany, Galenica AG, Bern, Switzerland (including Vifor SA, Villars-sur-Glâne, Switzerland), GlaxoSmithKline GmbH & Co. KG, Hamburg, Germany, Janssen-Cilag AG, Baar, Switzerland, Janssen-Cilag EMEA, Beerse, Belgium, Merck Sharp & Dohme-Chibret AG, Opfikon-Glattbrugg, Switzerland, Novo Nordisk A/S, Bagsvärd, Denmark, Octapharma AG, Lachen, Switzerland, Organon AG, Pfäffikon/SZ, Switzerland, Oxygen Biotherapeutics, Costa Mesa, CA, Pentapharm GmbH (now tem Innovations GmbH), Munich, Germany, ratiopharm Arzneimittel Vertriebs-GmbH, Vienna, Austria, Roche Pharma (Schweiz) AG, Reinach, Switzerland, Schering-Plough International, Inc., Kenilworth, New Jersey, USA, Vifor Pharma Deutschland GmbH, Munich, Germany, Vifor Pharma Österreich GmbH, Vienna, Austria, Vifor (International) AG, St. Gallen, Switzerland. ARG: Received honoraria or travel support for consulting or lecturing from the following companies: Allergan, Astra Zeneca, Eli Lilly, Merck Sharp & Dohme-Chibret AG, Pfizer, Sandoz AG, furthermore he received academic research grants from Allergan and Almirall. PS: Research Support: Swiss National Foundation; Janssen Cilag; Selo Foundation; „Erwin Schrödinger-Stipendium“, Research Funds of RehaClinic Bad Zurzach and the Cantonal Hospital Baden; Employee of RehaClinic Bad Zurzach; Consultant – Advisory Boards of Pfizer, Allergan; Speaker‘s Bureau – Allergan, Almirall, Pfizer.
Authors’ contributions
Conception and design: PS, CWS, KM, EA. Analysis and interpretation of the data: CWS, KM, ARG, PS, DMS, DRS, EA. Drafting of the article: CWS, KM, ARG, PS, DMS. Critical revision of the article for important intellectual content: PS, EA, DRS. Collection and assembly of data: CWS, PS. Statistical expertise: KR, KM, ARG. All authors read and approved the final manuscript.