Opioids and Migraine: Opioid Awareness and Frequency of Use among Turkish Migraineurs

Despite the inadequate evidence of effi cacy and safety of opioid use for the treatment of migraine, it has been reported that patients with moderate to severe migraine headaches are prescribed opioids. Migraineurs may experience serious health impacts from opioids such as headache-related disability, psychiatric and cardiovascular comorbidities. The reduction of the risk of opioid abuse and prevention of an opioid epidemic are important public health challenges. The aim of this study was to assess the awareness of opioid therapy for migraine and the frequency of use among Turkish patients with episodic and chronic migraine. Materials and methods: consecutive migraine patients were enrolled in this cross-sectional study. A semi-structured questionnaire was developed and used by the researchers to assess the patients’ awareness of an opiod treatment option and the frequency of use of opioids for migraine treatment. Results. One hundred two patients were enrolled, of which 72 had episodic migraine and 30 had chronic migraine. All subjects reported that they had not been offered or prescribed any kind of opioids by general practitioners and neurologists for their headache. Besides, only 7 % of patients declared that they had heard of opioid treatment for migraine but they had never consulted their doctors about its effects. Conclusions. Our fi ndings demonstrated that opioids were not preferred as an option for acute or preventive migraine treatment by Turkish migraineurs and their physicians. The reduction of opioid prescription will help to prevent the development of medication overuse and opiate-induced headaches and drug addiction.

Despite the inadequate evidence of effi cacy and safety of opioid use for the treatment of migraine, it has been reported that patients with severe migraine headaches are prescribed opioids for pain relief. Although the benefi ts are not supported by any evidence-based study, the use of opioids in migraine patients in emergency departments is quite common in countries such as the United States and Canada [6,7]. There have been studies evaluating opiophobia, prejudice against the use of opioid analgesics by patients and physicians, and the use of opioids for the management of cancer pain in Turkey [8,9]. However, the frequency of opi-oid use in Turkish migraineurs has not been well documented. The aim of this study was to assess the awareness of an opioid treatment option and the frequency of opioid use among Turkish patients with episodic and chronic migraine.

Study population and design
The study protocol was approved by the Research Ethics Committee at the University of Health Sciences, Sisli Hamidiye Etfal Research and Training Hospital and carried out in accordance with the Declaration of Helsinki. Written informed consents were obtained from all the participants. In this cross-sectional, clinicbased study, patients older than 18 years with episodic migraine (n = 72) and chronic migraine (n = 30) who had been followed in a neurology outpatient clinic from August 2018 to December 2018 were recruited prospectively. The diagnosis of headache was made based on neurological examination, neuroimaging studies, and all the diagnoses were made according to The International Classifi cation of Headache Disorders, 2018 (ICHD-3) [10].
Data on demographic and clinical characteristics such as age, gender, income, level of education, headache duration, headache severity (according to the numeric rating scale, 1 to 10), frequency and type of headaches in days, presence of medication overuse headache, and type of treatment were recorded. The results of all the subjects' physical and neurological examinations were normal. Patients who had been previously diagnosed by a professional with any other chronic health condition (i.e., neurological disorders other than migraine, endocrine disorders, mental illness, rheumatological disorders, cancer, etc.), patients with other types of headache disorders, as well as patients with comorbid headache disorders like migraine plus tension-type headache or other types of headache, were excluded.
The researchers relied on their professional experience to develop a semi-structured questionnaire consisting of 4 questions related to the aim of this study. The survey was conducted to assess the patients' awareness of opioid treatment and the frequency of opioid use for migraine.
The questions are listed below: 1. Do you know any prescription opioids used for pain relief?
2. Do you know any prescription opioids used for migraine type headaches?
3. Would you consider using opioid therapy for your migraine headache if it was prescribed by your doctor? 4. Have you been prescribed opioids for your migraine headache?

Statistical Analysis
Statistical analysis was performed using SPSS Statistics for Windows, version 23.0 (SPSS Inc., Chicago, Ill., USA). Descriptive statistics (mean, standard deviation, and frequency) were used to assess the demographic and clinical characteristics. Student's t-test was used to compare the mean values obtained for the two patient groups. The Chi-square test was used for categorical variables. A p value of <0.05 was considered to be statistically signifi cant.

RESULTS
One hundred two patients were enrolled, of which 72 had episodic migraine and 30 had chronic migraine. The mean age of the patients was 38.22 ± 9.06, 79 % of the patients were female. Twenty-three patients with chronic migraine had medication overuse headache (MOH). There were no statistically signifi cant diff er-ences in age, gender, education level, marital status, income, duration of migraine between the episodic and chronic migraine groups (all p values >0.05). Details of demographic and clinical characteristics of the subjects are given in Table 1.
The most commonly used analgesic for acute migraine attack treatment was paracetamol followed in order of frequency by non-steroidal anti-infl ammatory drugs (NSAIDs), paracetamol and caff eine combination tablets, and triptans. In the chronic migraine group, beta blockers (propranolol and metoprolol) were the most commonly used drugs for preventative treatment of migraine followed in order of frequency by antiepileptic drugs (topiramate, sodium valproate and lamotrigine), antidepressants (amitriptyline and venlafaxine), botulinum toxin injections, anaesthetic blockade of the greater occipital nerve, and calcium channel blockers (fl unarizine). Acute and preventive migraine treatments used by all the patients including the patients with chronic migraine are listed in Table 2.
According to the guidelines of the Turkish Ministry of Health on the prescription of opioids, both specialists and general practitioners are allowed to prescribe opioids. All the subjects who took part in the study reported that they had not been off ered or prescribed any kind of opioids by general practitioners, emergency physicians and neurologists for their headache. Besides, only 8 (7 %) patients declared that they had heard about the use of opioids for the treatment of migraine but they had never consulted their doctors about this. Table 3 summarises the responses of episodic and chronic migraine patients to the questionnaire aimed at assessing the patients' awareness of an opioid treatment option and the frequency of opioid use for migraine treatment. Примечание. * Для сравнения средних величин использовали t-критерий Стьюдента. ** Для категориальных переменных использовали критерий хи-квадрат.

DISCUSSION
The results of our study demonstrated that opioid therapy was not used as an option for acute or preventive migraine treatment by Turkish migraineurs. Furthermore, it was discovered that opioids were not prescribed and used by general practitioners, neurologists and emergency physicians. None of the patients had been prescribed opioids for their headache. This suggests that migraine chronicity had no connection with opioid use. Some studies report that both patients and physicians tend to avoid such drugs in the treatment of pain due to opiophobia in patients with chronic pain [8,9,11]. Opiophobia, defi ned as the irrational fear and prejudice against using opioids, is found among doctors because of the serious side eff ect profi le of these drugs and the need for close follow-up, and among patients due to their fear of stigmatization and being addicted to the drug [9]. The research on opiophobia in Turkish patients is based on identifi cation of opioid use for managing chronic cancer pain [9,11,12]. Although these stud-  Note. n -number of patients. * Some patients had more than one acute and/or preventive treatment.
Примечание. n -число пациентов. * Некоторые пациенты использовали несколько препаратов для купирования и/или профилактики приступов мигрени.  ies include a number of diff erent research methods and approaches, it can be concluded that over half of the patients with chronic pain have doubts about taking opioids and they are afraid of using morphine for their pain. According to the responses to the questionnaire we developed, a remarkable number of patients with migraine reported that they might use opioids if their doctors advised them to do so. It can be said that opiophobia in migraineurs is less common than opiophobia in patients with cancer pain. This can be explained by diff erent pain mechanisms of migraine and cancer pain, patients' clinical characteristics, comorbid disorders, cancer patients' fear, and severity of pain. In addition, this is the fi rst study exploring the frequency of Turkish migraineurs' use of opioid analgesic drugs for migraine and headache relief. Our patients stated that they had not been informed about such a treatment alternative. The fi ndings of the current study showed that chronicity of migraine, education level, gender, duration of headache, and medication overuse headache did not have any infl uence on the use of opioids for the acute and preventive (prophylactic) treatment of migraine. Even though there is not enough evidence, opioids are recommended only as second or third-line therapy for migraine -following simple analgesics, NSAIDs and migraine-specifi c medications such as triptans for moderate to severe migraine pain, and they should be reserved for emergency department use or rescue medication with limited use [13]. It is reported that opioids are one of the most common medications for acute migraine treatment in the USA and Canada emergency rooms [6,7]. However, opioid analgesics for migraine treatment are associated with more severe headacherelated disability, psychiatric and cardiovascular comorbidities, costs, and greater health-care resource utilization [14]. In a study by S.V. Tornabene et al., the researchers evaluated the use and timing of opioids for the treatment of migraine headaches in the emergency department. They reported that patients who received opioids for headache stayed in emergency rooms longer than patients who did not [15]. T.W. Ho et al investigated the eff ects of prior opioid use on rizatriptan effi cacy. They demonstrated that prior opioid use was associated with lower triptan response in migraine attacks [16]. S.J. Tepper stated that acute opioid use results in failure of migraine prevention [17]. Moreover, opioids are responsible for migraine progression [14]. EFNS and NICE guidelines do not recommend opioids for acute treatment of migraine 1 [5]. In this study, participants who visited the emergency department at least once for migraine attack treatment reported that they did not receive opioids.
Repeated morphine administration increases levels of calcitonin gene related peptide (CGRP) in the dorsal root ganglia in animal studies [18]. Upregulation of peripheral expression of CGRP in primary aff erent neurons of trigeminal ganglion might be the most important reason for increasing levels of pro-nociceptive peptide involved in migraine pathogenesis triggering the frequency of attacks [19]. This mechanism might explain how opioids play a role in the chronifi cation of migraine. It is well established that migraineurs are prone to developing chronic daily headaches namely chronic migraine or chronic tension-type headaches from opioid overuse [20,21]. In addition, the overuse of opioids for the treatment of migraine is related to medication overuse headache. The use of opioids eight days a month is a risk factor of medication overuse headache [8]. Taking into account that the patients were not off ered or prescribed opioid analgesics in the current study, we did not observe any association with chronifi cation of migraine and medication overuse headache.
Awareness and motivation campaigns against excessive opioid use are carried out in written and visual media around the world. Several studies in developed countries have recently highlighted that opioid use is an important public health problem, and stated the necessity of limiting the use of opioids [22][23][24]. D.C. Buse et al. assessed opioid use and dependence and found that 16.6 % of patients with chronic opioid use for migraine treatment met the dependence criteria and that these patients had more hospital admissions with more frequent recurrent complaints [25]. It is advisable that both patients and healthcare professionals should have realistic expectations of the intended benefi ts of treatment of chronic pain with opioids [26].

CONCLUSION
Opioid use is not a viable treatment option for Turkish patients with migraine. In order to raise awareness in our country, eff orts are being made in many areas, including social media, to protect young people from such substances and addictions. At the same time, there are substance addiction treatment centres which provide support to individuals who are opioid addicts as a result of medical and non-medical use. As the present study is a single-centre study, its results are limited in scope and off er only a general refl ection of the situation. However, our study was the fi rst to evaluate both episodic and chronic migraine patients' awareness of opioid use in the treatment of migraine and refl ected the perspectives of Turkish physicians and patients. Further studies of awareness of the general public and healthcare professionals about opioid use for the management of other headache types is warranted. It would be useful to understand the prevalence of opioid use for migraine treatment in other countries as well as views and opinions of professionals regarding the prescription practice.