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Efficacy of intravenous propacetamol hydrochloride in the treatment of an acute attack of migraine
European Journal of Internal Medicine 25 (2014) 629–632
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Efficacy of intravenous propacetamol hydrochloride in the treatment of an acute attack of migraine Aiwu Zhang a,1, Tao Jiang b,⁎,1, Yifeng Luo b, Zhenyang Zheng a, Xiaolei Shi a, Zijian Xiao a, Yannan Fang a,⁎⁎ a b
Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Second Zhongshang Road, Guangzhou 510080, China Department of Neurology, The Third Affiliated Hospital of Southern Medical University, No. 183, Zhongshan Road West, Guangzhou 510630, China
a r t i c l e
i n f o
Article history: Received 20 February 2014 Received in revised form 3 June 2014 Accepted 7 June 2014 Available online 5 July 2014 Keywords: Propacetamol Rizatriptan Triptans Migraine Headache Efficacy
a b s t r a c t Background: Triptans are a family of selective serotonin (5-HT1B/1D) receptor agonists that are widely used to treat acute migraine attacks. Their efficacy is limited by side effects and the gastrointestinal manifestations of migraine. Aim: To compare the efficacy of a single intravenous administration of propacetamol, a prodrug of paracetamol (acetaminophen) with a single dose of oral rizatriptan in treating acute migraine attacks. Methods: Patients were selected from those who presented to the emergency room with a diagnosed migraine attack and who had not previously taken any analgesics. They were randomized into 2 groups: treatment with a single 1 g IV dose of propacetamol or with a single oral dose of 5 mg rizatriptan. Their Visual Analogue Scale (VAS) pain scores were assessed before and at 30, 60, and 120 min after treatment. Results: The patients who received the propacetamol had significantly improved VAS scores at 60 min compared to the rizatriptan group. There were no significant differences in VAS scores at 30 or 120 min post-treatment. Conclusion: Propacetamol is either equivalent or superior in efficacy to rizatriptan for treating acute migraine attacks, while having the advantage of parenteral administration in patients whose migraines are accompanied by nausea and vomiting. © 2014 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
1. Introduction Headaches are an exceedingly common complaint in primary care, accounting for millions of visits to primary care providers and emergency departments each year [1]. Migraine is a particular type of headache characterized by recurrent attacks of severe, throbbing, unilateral pain and often accompanied by nausea, vomiting and photo- or phonophobia [2,3]. These headaches are considered to be a chronic pain syndrome and a health issue which creates a huge burden on both the migraine sufferer and the society in terms of lost income, productivity and healthcare costs [4,5]. Depending on geographical location and classification criteria, the prevalence of migraine is found to range from 0.6– 1.7% in Asia [6] to 6–18% in North America [4,7] with women affected almost 3 times as often as men [4].
⁎ Correspondence to: T. Jiang, Department of Neurology, The Third Affiliated Hospital of Southern Medical University, No. 183, Zhongshan Road West, Guangzhou 510630, China. Tel.: +86 13711245792. ⁎⁎ Correspondence to: Y. Fang, Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Second Zhongshang Road, Guangzhou 510080, China. Tel./ fax: +86 87330441. E-mail addresses: [email protected] (T. Jiang), [email protected] (Y. Fang). 1 Zhang Aiwu and Jiang Tao contributed equally to this study.
In some population studies it is estimated that 50–75% of patients suffer substantial disability with their migraines, including the need for bed rest [8]. Multiple studies have reported substantial burdens on healthcare utilization, personal productivity and quality of life due to headache [9,10]. The etiology of migraine isn't clearly understood but is known to be multifactorial and includes neurovascular factors including vasodilation. In the past ergot derivatives, which act primarily via vasoconstriction were the only specific treatment options for migraine. Many patients self-treat their migraines with simple OTC analgesics such as paracetamol (acetaminophen) and nonsteroidal anti-inflammatory agent (NSAIDS). Triptans, a family of selective serotonin (5-HT1B/1D) receptor agonists, are believed to work by blocking the production of vasoactive peptides and aborting the cascade of events associated with a migraine attack [2,11]. These drugs have become a mainstay of treatment of acute migraine attacks. They have demonstrated clinical efficacy in many clinical trials and have the advantages of ease of administration and rapid onset of action [2,12,13]. However, there are several problems, which limit their efficacy. Nausea, vomiting, and gastroparesis associated with migraines reduce gastric absorption of the drug [14,15]. The drugs are most effective when taken early in the attack and often by the time patients recognize that they are having a migraine attack
http://dx.doi.org/10.1016/j.ejim.2014.06.007 0953-6205/© 2014 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
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A. Zhang et al. / European Journal of Internal Medicine 25 (2014) 629–632
(as opposed to, say, an “ordinary headache”) the window of opportunity has past. In addition, because of their vasoconstrictive action, there is a small risk of cardiovascular side effects including vasospastic angina [2,16]. Finally, only one triptan is available in the local [Chinese] market. For these reasons, parenteral analgesia with a drug with few side effects and easy availability would be ideal. Paracetamol (acetaminophen) and its prodrug propacetamol are two commonly used analgesics that are available intravenously and have shown variable efficacy in clinical trials for a variety of pain syndromes [17–19]. One randomized placebo-control study of intravenous acetaminophen for migraine showed no benefit of acetaminophen over placebo (although both groups had a very high rate of headache remission, indicative, perhaps, of the natural history of migraine attacks) [20]. Propacetamol is readily available in the local market and has relatively few side effects. In addition, it is not associated with cardiovascular complications and its parenteral use makes it ideal in patients suffering from nausea and vomiting as well as the gastroparesis that often accompanies migraines. For this reason, intravenous administration of this drug in the setting of acute migraine attack may prove to be as effective as or more effective than the use of oral triptans. In a search of the literature, no studies were found specifically comparing propacetamol to triptans for the treatment of acute migraine. This study is novel in that we did a head to head comparison of intravenous propacetamol and oral rizatriptan in the treatment of acute migraine attacks in the emergency setting. We hypothesized that propacetamol would be at least as effective as oral rizatriptan in this context. 2. Methodology 2.1. Study subjects Patients were selected from those who visited the emergency department (ED) of the First Affiliated Hospital of Sun Yat-sen University with an acute migraine attack during the period from January 2012 to June 2012. The hospital ethics committees approved the study and patients were informed in writing of the purpose and methods of the study. They were informed that they would be given medication for migraine and that they would be observed in the ED after being given the medication. The patients then gave their written consent to participate in the study. Patients were diagnosed with migraine according to the 2004 International Headache Society criteria [21]. They were diagnosed with migraine with or without aura and had no neurologic deficits on physical examination and no abnormalities on CT scanning. Patients were included if they met the diagnostic criteria and had the following characteristics: previous migraine diagnosis for at least a year, at least 5 prior episodes of migraine, and no fewer than 3 episodes in a year. The current headache episode itself met the following criteria: duration of pain for at least 3 h, Visual Analogue Scale (VAS) pain score of at least 6/10, pain unilateral and pulsatile in character, accompanied by nausea and vomiting, worsened by increased activity, and pain severely impacting on work and/or study. Patients who had had a history or symptoms of ischemic heart disease, ischemic cerebrovascular disease, ischemic peripheral vascular disease, severe heart, liver or kidney dysfunction, uncontrolled hypertension, and history of drug allergies were excluded. Pregnant and lactating women and those who had taken pain medications within 24 h were also excluded. 2.2. Study design The study was a randomized controlled trial with two treatment arms; IV propacetamol and oral rizatriptan benzoate. The patients were blinded to the treatment they received and VAS score raters (who were doctoral students) were blinded as to the treatment the
patients received. The doctors diagnosing and treating the patients were not blinded. 2.3. Study protocol and data collection Patients presenting to the emergency room for an acute attack of migraine during the study period were selected for the study using the given criteria. Using a pre-generated order of random number table, the patients were randomized into two treatment groups. Patients in the propacetamol group were given propacetamol 1 g dissolved in 100 ml NS and infused intravenously over 30 min. Patients in the rizatriptan group were given rizatriptan benzoate 5 mg tablet once orally. VAS pain scores (0 to 10 points, 0 indicating no pain and 10 indicating most intense pain possible or unbearable pain) were assessed before and 30, 60, and 120 min after treatment. The patients remained under observation for up to 24 h and were discharged once their headache had remitted. At discharge, they were prescribed the conventional medication of Sibelium 5–10 mg once daily for maintenance prophylaxis of migraine. The study participants were not specifically observed for side effects. 2.4. Statistical analysis Statistical analyses were done using SPSS (version 20) with an alpha level of 0.05. Continuous variables were reported as mean +/− SD. The categorical variables were reported as number and percentage. Independent-sample t-test and chi-square tests were used to assess differences between groups in regard to demographic and baseline clinical information. Study endpoints (pain relief at 30, 60 and 120 min) were analyzed with the generalized estimating equation (GEE) model to account for the within-subject variability over time and multiple measurements. In order to determine if there were gender differences in pain relief, we conducted another GEE model and included gender as a covariate. 3. Results A total of 148 patients were included in the study with 75 patients in the rizatriptan group and 73 patients in the propacetamol group. Table 1 shows the demographic and baseline clinical characteristics of the patients. There was no significant difference between the groups in age, duration of the attack or acute migraine history, sex, pain location, pain quality, associated symptoms, medications taken prior to the visit or baseline VAS score. Results of the regression analysis using GEE are presented in Table 2. After adjusting for the variables in Table 1, it was found that pain relief in the two groups significantly differed at 60 min after treatment, with propacetamol showing significantly better efficacy over rizatriptan (β = 0.41, P b 0.001). There were no differences in pain relief between the two groups at 30 and 120 min post-treatment. In addition, the results revealed no statistically significant differences in pain relief between male and female patients (β = 0.079, P = 0.106). 4. Discussion Migraine is a chronic and debilitating syndrome characterized by attacks of moderate to severe head pain and often accompanied by nausea, vomiting, photophobia and sometimes aura [3,12]. The pathophysiology of migraine is still being worked out but is known to be multifactorial and includes neurovascular factors including vasodilation. In the past, ergot derivatives, which act primarily via vasoconstriction, were the only specific treatment options for migraine. For this reason, treatment options have not always been specific enough to treat the underlying causes and mitigate symptoms effectively with minimal side effects [3,11,12]. The development of the triptan family of drugs was a significant advance in the treatment of migraine, as they seem to target
A. Zhang et al. / European Journal of Internal Medicine 25 (2014) 629–632
631
Table 1 Demographic information and baseline characteristic comparisons between the two patient groups.
Gender, n (%) Male Female Age, mean (SD) years Duration of present attack, mean (SD) hours Acute migraine history, mean (SD) years Pain location, n (%) One-sided Two-sided Type of pain, n (%) Throbbing Non-throbbing Concomitant symptoms, n (%) Nausea/vomiting Both Concomitant medications, n (%) Luminal Metoclopramide None Baseline VAS score, n (%) Mild Moderate Severe
Rizatriptan group (n = 75)
Propacetamol group (n = 73)
P-value
31 (41.3) 44 (58.7) 36.6 (12.8) 3.3 (1.5) 5.0 (2.9)
41 (56.2) 32 (43.8) 35.6 (10.8) 3.4 (1.6) 5.5 (3.2)
n.s.
67 (89.3) 8 (10.7)
63 (86.3) 10 (13.7)
n.s.
68 (90.7) 7 (9.3)
70 (95.9) 3 (4.1)
n.s.
73 (97.3) 2 (2.7)
70 (95.9) 3 (4.1)
n.s.
26 (34.7) 23 (30.6) 26 (34.7)
29 (39.7) 20 (27.4) 24 (32.9)
n.s.
0 24 (32.0) 51 (68.0)
0 21 (28.8) 52 (71.2)
n.s.
n.s. n.s. n.s.
Abbreviations: VAS, Visual Analogue Scale; n.s., non-significance.
some of the specific causes of migraine and have the advantages of being easy to self-administer, fairly quick acting and effective [2,11, 13]. However, because they are, in most cases, orally administered, their efficacy can be limited in the large number of patients who experience nausea and vomiting or whose migraines are accompanied by gastroparesis and therefore their gastric absorption is impaired [14]. In addition, in the local market, there is only one triptan available. The use of an IV analgesic, such as propacetamol, which has few side effects, would be a way around this problem. This study compared a single dose of propacetamol IV to a single oral dose of rizatriptan. In follow-up observations, the propacetamol showed superior efficacy at 1 h and there was no significant difference at 30 min or at 2 h. This indicates that IV propacetamol is at least as effective, if not more so than rizatriptan in the treatment of acute migraine attacks. Up until now, there have been limited studies comparing the efficacy of various triptans to each other and no studies comparing triptans to treatment with intravenous propacetamol. Our study showed parenteral propacetamol to be as effective as oral rizatriptan in aborting an acute migraine attack. This is consistent with previous studies demonstrating
Table 2 Pain relief at 30 min, 60 min, and 120 min after the application of the study medication.
Pain relief at 30 min Rizatriptan Propacetamol Pain relief at 60 min Rizatriptan Propacetamol Pain relief at 120 min Rizatriptan Propacetamol
β
SE
– 0.03
– 0.07
.645
– 0.41
– 0.08
b.001
– −0.05
– 0.07
.535
the efficacy of propacetamol in treating acute pain in general and specifically in treating acute migraine attacks [17–20]. Add to this the limitations to providing treatment with oral triptans [2,14,15] and the novel findings of this study are significant. In addition, because of the substantial burden on patients, the healthcare system and society of chronic migraine, this study has significant applicability to the clinical setting. One limitation of this study was the selection of patients who had not already self-administered triptans or other medications prior to their arrival in the ED. In actual clinical practice it is likely that this is an unusual occurrence. A survey of patients in Spain indicated that many patients self-medicate with analgesics, NSAIDs or triptans upon the onset of headache [8]. Other studies have indicated that up to 50% of migraine sufferers in the US and the UK had not contacted a doctor about their symptoms in the past year and between 14 and 31% of patients had never consulted a doctor [5]. However, it is estimated that more than 50% of patients self-medicate their migraines with various types of medications [5,8]. Assuming some applicability of these findings to the Asian population, this would suggest that the study population used in this study might be somewhat biased. It is unclear whether the subset of patients who had not already self-medicated prior to an ED might be substantively different from those patients who only visited an ED after trying to medicate their headache at home. In particular, the latter group of patients may indeed have a more severe or refractory type of headache and therefore their results may vary substantially from the group investigated in this study. This is an area for further study.
P-value
Abbreviations: SE, standard error; n.s., non-significance. β values pertain to the interaction term in the GEE model (pain relief × time) and reflect effectiveness of propacetamol compared with that of rizatriptan with positive β indicating better efficacy. Variables in the GEE model included age, duration of the attack, acute migraine history, sex, pain location, pain quality, associated symptoms, medications taken prior to the visit, and baseline VAS score.
5. Conclusion Intravenous propacetamol is a promising treatment option for acute migraine attacks in the emergency setting, as it is safe and effective even in the presence of nausea and vomiting which so often accompany migraine. Its efficacy has been found to be equal to or greater than that of rizatriptan. Further research is necessary to refine the population most likely to benefit from this intervention.
Conflict of interests The authors declare that they have no competing interests.
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Acknowledgments This work was supported by the Guangdong Medical Research Foundation (No. B2013295) and the National Natural Science Foundation of China (No. 81171101). References [1] International Association for the Study of Pain. Global Year Against Headache Oct 2011–Oct 2012. Epidemiol Headache 2011;25:29–31. [2] Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT1B/1D agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 2001;358:1668–75. [3] Ferrari MD. Migraine. Lancet 1998;351:1043–51. [4] Lipton RB, Bigal ME. The epidemiology of migraine. Am J Med 2005;118:3S–10S. [5] Lipton RB, Scher AI, Steiner TJ, Bigal ME, Kolodner K, Liberman JN, et al. Patterns of healthcare utilization for migraine in England and the US. Neurology 2003;60:441–8. [6] Stark RJ, Ravishankar K, Siow HC, Lee KS, Pepperle R, Wang SJ. Chronic migraine and chronic daily headache in the Asia-Pacific region: a systematic review. Cephalgia 2012;33:266–83. [7] Manzoni GC, Torelli P. Epidemiology of migraine. J Headache Pain 2001;2:S11–3. [8] Hernansanz MAC, Roy RS, Orgaz AC, López-Gil A. Migraine treatment patterns and patient satisfaction with prior therapy: a substudy of a multicenter trial of rizatriptan effectiveness. Clin Ther 2003;25:2053–69. [9] Lipton RB, Bigal ME, Scher AI, Stewart WF. The global burden of migraine. J Headache Pain 2003;4:S3–S11. [10] Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the US: data from the American Migraine Study II. Headache 2001;41:646–57.
[11] Loder E. Triptan therapy in migraine. N Engl J Med 2010;363:63–70. [12] Goadsby PJ, Lipton RB, Ferrari MD. Migraine—current understanding and treatment. N Engl J Med 2002;346:257–70. [13] Ng-Mak DS, Hu H, Chen Y-T, Ma L. Acute migraine treatment with oral triptans and NSAIDs in a managed care population. Headache 2008;48:1176–85. [14] Pierce M. Oral triptans and nausea: treatment considerations in migraine. Headache 2013;53:17–20. [15] Newman LC. Why triptan treatment can fail: focus on gastrointestinal manifestations of migraine. Headache 2013;53:11–6. [16] Hall GC, Brown MM, Mo J, MacRae KD. Triptans in migraine: the risks of stroke, cardiovascular disease, and death in practice. Neurology 2004;62:563–8. [17] Jebaraj B, Maitra S, Baidya DK, Khanna P. Intravenous paracetamol reduces postoperative opioid consumption after orthopedic surgery: a systematic review of clinical trials. Pain Res Treat 2013;2013:1–6. [18] Walson P, Jones J, Chesney R, Rodarte A. Antipyretic efficacy and tolerability of a single intravenous dose of the acetaminophen prodrug propacetamol in children: a randomized, double-blind, placebo-controlled trial. Clin Ther 2006;28:762–9. [19] McNicol ED, Tzortzopoulou A, Cepeda MS, Francia MBD, Farhat T, Schumann R. Single dose intravenous propacetamol or intravenous paracetamol for postoperative pain (review). British Journal of AnaesthesiaOxford University Press; 2011. p. 1–12. [20] Leinisch E, Evers S, Kaempfe N, Kraemer C, Sostak P, Jürgens T, et al. Evaluation of the efficacy of intravenous acetaminophen in the treatment of acute migraine attacks: a double-blind, placebo-controlled parallel group multicenter study. Pain 2005;117:396–400. [21] The Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders. 2nd ed. International Headache Society; 2004 1–20.
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Efficacy of intravenous propacetamol hydrochloride in the treatment of an acute attack of migraine Aiwu Zhang a,1, Tao Jiang b,⁎,1, Yifeng Luo b, Zhenyang Zheng a, Xiaolei Shi a, Zijian Xiao a, Yannan Fang a,⁎⁎ a b
Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Second Zhongshang Road, Guangzhou 510080, China Department of Neurology, The Third Affiliated Hospital of Southern Medical University, No. 183, Zhongshan Road West, Guangzhou 510630, China
a r t i c l e
i n f o
Article history: Received 20 February 2014 Received in revised form 3 June 2014 Accepted 7 June 2014 Available online 5 July 2014 Keywords: Propacetamol Rizatriptan Triptans Migraine Headache Efficacy
a b s t r a c t Background: Triptans are a family of selective serotonin (5-HT1B/1D) receptor agonists that are widely used to treat acute migraine attacks. Their efficacy is limited by side effects and the gastrointestinal manifestations of migraine. Aim: To compare the efficacy of a single intravenous administration of propacetamol, a prodrug of paracetamol (acetaminophen) with a single dose of oral rizatriptan in treating acute migraine attacks. Methods: Patients were selected from those who presented to the emergency room with a diagnosed migraine attack and who had not previously taken any analgesics. They were randomized into 2 groups: treatment with a single 1 g IV dose of propacetamol or with a single oral dose of 5 mg rizatriptan. Their Visual Analogue Scale (VAS) pain scores were assessed before and at 30, 60, and 120 min after treatment. Results: The patients who received the propacetamol had significantly improved VAS scores at 60 min compared to the rizatriptan group. There were no significant differences in VAS scores at 30 or 120 min post-treatment. Conclusion: Propacetamol is either equivalent or superior in efficacy to rizatriptan for treating acute migraine attacks, while having the advantage of parenteral administration in patients whose migraines are accompanied by nausea and vomiting. © 2014 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
1. Introduction Headaches are an exceedingly common complaint in primary care, accounting for millions of visits to primary care providers and emergency departments each year [1]. Migraine is a particular type of headache characterized by recurrent attacks of severe, throbbing, unilateral pain and often accompanied by nausea, vomiting and photo- or phonophobia [2,3]. These headaches are considered to be a chronic pain syndrome and a health issue which creates a huge burden on both the migraine sufferer and the society in terms of lost income, productivity and healthcare costs [4,5]. Depending on geographical location and classification criteria, the prevalence of migraine is found to range from 0.6– 1.7% in Asia [6] to 6–18% in North America [4,7] with women affected almost 3 times as often as men [4].
⁎ Correspondence to: T. Jiang, Department of Neurology, The Third Affiliated Hospital of Southern Medical University, No. 183, Zhongshan Road West, Guangzhou 510630, China. Tel.: +86 13711245792. ⁎⁎ Correspondence to: Y. Fang, Department of Neurology, The First Affiliated Hospital of Sun Yat-sen University, No. 58, Second Zhongshang Road, Guangzhou 510080, China. Tel./ fax: +86 87330441. E-mail addresses: [email protected] (T. Jiang), [email protected] (Y. Fang). 1 Zhang Aiwu and Jiang Tao contributed equally to this study.
In some population studies it is estimated that 50–75% of patients suffer substantial disability with their migraines, including the need for bed rest [8]. Multiple studies have reported substantial burdens on healthcare utilization, personal productivity and quality of life due to headache [9,10]. The etiology of migraine isn't clearly understood but is known to be multifactorial and includes neurovascular factors including vasodilation. In the past ergot derivatives, which act primarily via vasoconstriction were the only specific treatment options for migraine. Many patients self-treat their migraines with simple OTC analgesics such as paracetamol (acetaminophen) and nonsteroidal anti-inflammatory agent (NSAIDS). Triptans, a family of selective serotonin (5-HT1B/1D) receptor agonists, are believed to work by blocking the production of vasoactive peptides and aborting the cascade of events associated with a migraine attack [2,11]. These drugs have become a mainstay of treatment of acute migraine attacks. They have demonstrated clinical efficacy in many clinical trials and have the advantages of ease of administration and rapid onset of action [2,12,13]. However, there are several problems, which limit their efficacy. Nausea, vomiting, and gastroparesis associated with migraines reduce gastric absorption of the drug [14,15]. The drugs are most effective when taken early in the attack and often by the time patients recognize that they are having a migraine attack
http://dx.doi.org/10.1016/j.ejim.2014.06.007 0953-6205/© 2014 Published by Elsevier B.V. on behalf of European Federation of Internal Medicine.
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A. Zhang et al. / European Journal of Internal Medicine 25 (2014) 629–632
(as opposed to, say, an “ordinary headache”) the window of opportunity has past. In addition, because of their vasoconstrictive action, there is a small risk of cardiovascular side effects including vasospastic angina [2,16]. Finally, only one triptan is available in the local [Chinese] market. For these reasons, parenteral analgesia with a drug with few side effects and easy availability would be ideal. Paracetamol (acetaminophen) and its prodrug propacetamol are two commonly used analgesics that are available intravenously and have shown variable efficacy in clinical trials for a variety of pain syndromes [17–19]. One randomized placebo-control study of intravenous acetaminophen for migraine showed no benefit of acetaminophen over placebo (although both groups had a very high rate of headache remission, indicative, perhaps, of the natural history of migraine attacks) [20]. Propacetamol is readily available in the local market and has relatively few side effects. In addition, it is not associated with cardiovascular complications and its parenteral use makes it ideal in patients suffering from nausea and vomiting as well as the gastroparesis that often accompanies migraines. For this reason, intravenous administration of this drug in the setting of acute migraine attack may prove to be as effective as or more effective than the use of oral triptans. In a search of the literature, no studies were found specifically comparing propacetamol to triptans for the treatment of acute migraine. This study is novel in that we did a head to head comparison of intravenous propacetamol and oral rizatriptan in the treatment of acute migraine attacks in the emergency setting. We hypothesized that propacetamol would be at least as effective as oral rizatriptan in this context. 2. Methodology 2.1. Study subjects Patients were selected from those who visited the emergency department (ED) of the First Affiliated Hospital of Sun Yat-sen University with an acute migraine attack during the period from January 2012 to June 2012. The hospital ethics committees approved the study and patients were informed in writing of the purpose and methods of the study. They were informed that they would be given medication for migraine and that they would be observed in the ED after being given the medication. The patients then gave their written consent to participate in the study. Patients were diagnosed with migraine according to the 2004 International Headache Society criteria [21]. They were diagnosed with migraine with or without aura and had no neurologic deficits on physical examination and no abnormalities on CT scanning. Patients were included if they met the diagnostic criteria and had the following characteristics: previous migraine diagnosis for at least a year, at least 5 prior episodes of migraine, and no fewer than 3 episodes in a year. The current headache episode itself met the following criteria: duration of pain for at least 3 h, Visual Analogue Scale (VAS) pain score of at least 6/10, pain unilateral and pulsatile in character, accompanied by nausea and vomiting, worsened by increased activity, and pain severely impacting on work and/or study. Patients who had had a history or symptoms of ischemic heart disease, ischemic cerebrovascular disease, ischemic peripheral vascular disease, severe heart, liver or kidney dysfunction, uncontrolled hypertension, and history of drug allergies were excluded. Pregnant and lactating women and those who had taken pain medications within 24 h were also excluded. 2.2. Study design The study was a randomized controlled trial with two treatment arms; IV propacetamol and oral rizatriptan benzoate. The patients were blinded to the treatment they received and VAS score raters (who were doctoral students) were blinded as to the treatment the
patients received. The doctors diagnosing and treating the patients were not blinded. 2.3. Study protocol and data collection Patients presenting to the emergency room for an acute attack of migraine during the study period were selected for the study using the given criteria. Using a pre-generated order of random number table, the patients were randomized into two treatment groups. Patients in the propacetamol group were given propacetamol 1 g dissolved in 100 ml NS and infused intravenously over 30 min. Patients in the rizatriptan group were given rizatriptan benzoate 5 mg tablet once orally. VAS pain scores (0 to 10 points, 0 indicating no pain and 10 indicating most intense pain possible or unbearable pain) were assessed before and 30, 60, and 120 min after treatment. The patients remained under observation for up to 24 h and were discharged once their headache had remitted. At discharge, they were prescribed the conventional medication of Sibelium 5–10 mg once daily for maintenance prophylaxis of migraine. The study participants were not specifically observed for side effects. 2.4. Statistical analysis Statistical analyses were done using SPSS (version 20) with an alpha level of 0.05. Continuous variables were reported as mean +/− SD. The categorical variables were reported as number and percentage. Independent-sample t-test and chi-square tests were used to assess differences between groups in regard to demographic and baseline clinical information. Study endpoints (pain relief at 30, 60 and 120 min) were analyzed with the generalized estimating equation (GEE) model to account for the within-subject variability over time and multiple measurements. In order to determine if there were gender differences in pain relief, we conducted another GEE model and included gender as a covariate. 3. Results A total of 148 patients were included in the study with 75 patients in the rizatriptan group and 73 patients in the propacetamol group. Table 1 shows the demographic and baseline clinical characteristics of the patients. There was no significant difference between the groups in age, duration of the attack or acute migraine history, sex, pain location, pain quality, associated symptoms, medications taken prior to the visit or baseline VAS score. Results of the regression analysis using GEE are presented in Table 2. After adjusting for the variables in Table 1, it was found that pain relief in the two groups significantly differed at 60 min after treatment, with propacetamol showing significantly better efficacy over rizatriptan (β = 0.41, P b 0.001). There were no differences in pain relief between the two groups at 30 and 120 min post-treatment. In addition, the results revealed no statistically significant differences in pain relief between male and female patients (β = 0.079, P = 0.106). 4. Discussion Migraine is a chronic and debilitating syndrome characterized by attacks of moderate to severe head pain and often accompanied by nausea, vomiting, photophobia and sometimes aura [3,12]. The pathophysiology of migraine is still being worked out but is known to be multifactorial and includes neurovascular factors including vasodilation. In the past, ergot derivatives, which act primarily via vasoconstriction, were the only specific treatment options for migraine. For this reason, treatment options have not always been specific enough to treat the underlying causes and mitigate symptoms effectively with minimal side effects [3,11,12]. The development of the triptan family of drugs was a significant advance in the treatment of migraine, as they seem to target
A. Zhang et al. / European Journal of Internal Medicine 25 (2014) 629–632
631
Table 1 Demographic information and baseline characteristic comparisons between the two patient groups.
Gender, n (%) Male Female Age, mean (SD) years Duration of present attack, mean (SD) hours Acute migraine history, mean (SD) years Pain location, n (%) One-sided Two-sided Type of pain, n (%) Throbbing Non-throbbing Concomitant symptoms, n (%) Nausea/vomiting Both Concomitant medications, n (%) Luminal Metoclopramide None Baseline VAS score, n (%) Mild Moderate Severe
Rizatriptan group (n = 75)
Propacetamol group (n = 73)
P-value
31 (41.3) 44 (58.7) 36.6 (12.8) 3.3 (1.5) 5.0 (2.9)
41 (56.2) 32 (43.8) 35.6 (10.8) 3.4 (1.6) 5.5 (3.2)
n.s.
67 (89.3) 8 (10.7)
63 (86.3) 10 (13.7)
n.s.
68 (90.7) 7 (9.3)
70 (95.9) 3 (4.1)
n.s.
73 (97.3) 2 (2.7)
70 (95.9) 3 (4.1)
n.s.
26 (34.7) 23 (30.6) 26 (34.7)
29 (39.7) 20 (27.4) 24 (32.9)
n.s.
0 24 (32.0) 51 (68.0)
0 21 (28.8) 52 (71.2)
n.s.
n.s. n.s. n.s.
Abbreviations: VAS, Visual Analogue Scale; n.s., non-significance.
some of the specific causes of migraine and have the advantages of being easy to self-administer, fairly quick acting and effective [2,11, 13]. However, because they are, in most cases, orally administered, their efficacy can be limited in the large number of patients who experience nausea and vomiting or whose migraines are accompanied by gastroparesis and therefore their gastric absorption is impaired [14]. In addition, in the local market, there is only one triptan available. The use of an IV analgesic, such as propacetamol, which has few side effects, would be a way around this problem. This study compared a single dose of propacetamol IV to a single oral dose of rizatriptan. In follow-up observations, the propacetamol showed superior efficacy at 1 h and there was no significant difference at 30 min or at 2 h. This indicates that IV propacetamol is at least as effective, if not more so than rizatriptan in the treatment of acute migraine attacks. Up until now, there have been limited studies comparing the efficacy of various triptans to each other and no studies comparing triptans to treatment with intravenous propacetamol. Our study showed parenteral propacetamol to be as effective as oral rizatriptan in aborting an acute migraine attack. This is consistent with previous studies demonstrating
Table 2 Pain relief at 30 min, 60 min, and 120 min after the application of the study medication.
Pain relief at 30 min Rizatriptan Propacetamol Pain relief at 60 min Rizatriptan Propacetamol Pain relief at 120 min Rizatriptan Propacetamol
β
SE
– 0.03
– 0.07
.645
– 0.41
– 0.08
b.001
– −0.05
– 0.07
.535
the efficacy of propacetamol in treating acute pain in general and specifically in treating acute migraine attacks [17–20]. Add to this the limitations to providing treatment with oral triptans [2,14,15] and the novel findings of this study are significant. In addition, because of the substantial burden on patients, the healthcare system and society of chronic migraine, this study has significant applicability to the clinical setting. One limitation of this study was the selection of patients who had not already self-administered triptans or other medications prior to their arrival in the ED. In actual clinical practice it is likely that this is an unusual occurrence. A survey of patients in Spain indicated that many patients self-medicate with analgesics, NSAIDs or triptans upon the onset of headache [8]. Other studies have indicated that up to 50% of migraine sufferers in the US and the UK had not contacted a doctor about their symptoms in the past year and between 14 and 31% of patients had never consulted a doctor [5]. However, it is estimated that more than 50% of patients self-medicate their migraines with various types of medications [5,8]. Assuming some applicability of these findings to the Asian population, this would suggest that the study population used in this study might be somewhat biased. It is unclear whether the subset of patients who had not already self-medicated prior to an ED might be substantively different from those patients who only visited an ED after trying to medicate their headache at home. In particular, the latter group of patients may indeed have a more severe or refractory type of headache and therefore their results may vary substantially from the group investigated in this study. This is an area for further study.
P-value
Abbreviations: SE, standard error; n.s., non-significance. β values pertain to the interaction term in the GEE model (pain relief × time) and reflect effectiveness of propacetamol compared with that of rizatriptan with positive β indicating better efficacy. Variables in the GEE model included age, duration of the attack, acute migraine history, sex, pain location, pain quality, associated symptoms, medications taken prior to the visit, and baseline VAS score.
5. Conclusion Intravenous propacetamol is a promising treatment option for acute migraine attacks in the emergency setting, as it is safe and effective even in the presence of nausea and vomiting which so often accompany migraine. Its efficacy has been found to be equal to or greater than that of rizatriptan. Further research is necessary to refine the population most likely to benefit from this intervention.
Conflict of interests The authors declare that they have no competing interests.
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