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Randomized evaluation of octreotide vs prochlorperazine for ED treatment of migraine headache
American Journal of Emergency Medicine (2009) 27, 160–164
www.elsevier.com/locate/ajem
Original Contribution
Randomized evaluation of octreotide vs prochlorperazine for ED treatment of migraine headache☆ Michael A. Miller MD a,⁎, Marc E. Levsky MD b , William Enslow DO a , Alex Rosin MD b a
Department of Emergency Medicine, Tripler Army Medical Center, Honolulu Hawaii, 96859, USA Department of Emergency Medicine, Carl R. Darnall Army Medical Center, Ft Hood, TX 76544, USA
b
Received 5 November 2007; revised 24 December 2007; accepted 22 January 2008
Abstract Patients with headaches account for approximately 2% of all ED visits, with migraines being the most common defined primary headache syndrome. Our goals were to evaluate the efficacy of intravenous octreotide (OC) for the treatment of migraines, when compared to standard therapy with prochlorperazine. Methods: The study was conducted as a double-blinded, randomized controlled trial. Each subject received either 100 μg of octreotide or 10 mg of prochlorperazine intravenously for a 2-minute period. Results: Comparison of the change in median visual analog scale scores for 60 minutes demonstrated that octreotide was less effective at reducing pain (P = .03) and producing clinical success (P b .01). Restlessness consistent with akathisia was noted by 35% of the PC group and 8% of the OC group (P b .01). At 60 minutes, rescue medication was required by 48% of the patients in the OC group, whereas 10% of the PC group required such therapy (P b .01). All 44 patients were contacted for follow-up at 48 to 72 hours after enrollment. At that time, 10% of the prochlorperazine and 25% of the octreotide patients had experienced some headache recurrence (P = .1). Conclusion: Prochlorperazine was statistically superior to octreotide in clinical success rate and decrease in pain in migraine patients but caused more restlessness and sedation. © 2009 Published by Elsevier Inc.
1. Introduction 1.1. Background Patients with headaches account for approximately 2% of all emergency department (ED) visits, with migraines being the most common defined primary headache syndrome [1-3]. Patients presenting to the ED often have failed outpatient Presented at the ACEP Scientific Assembly, Seattle, WA, October 2007. ☆ This work is the opinion of the authors and does not necessarily represent the opinion of the U.S. Army or the Department of Defense. ⁎ Corresponding author. Tel.: +1 254 288 8303; fax: +1 254 286 7055. E-mail address: [email protected] (M.A. Miller). 0735-6757/$ – see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.ajem.2008.01.015
therapy and exhibit severe and persistent symptoms. Treatment options have expanded, but patients are still often met with the frustrating failures of pharmaceutical intervention. In 1986, a nonopioid, prochlorperazine (PC), was noted serendipitously to relieve acute migraine headache pain [4]. Prochlorperazine has been successfully used to treat migraine headaches for the past several decades and has been accepted as a first-line treatment of headaches in many EDs often used as a comparative group for clinical trials comparing pharmaceutical efficacy [1,5-9]. Unfortunately, PC frequently causes side effects including dysphoria, drowsiness, akathisia, and extrapyramidal effects [5,8,10]. In the past, intravenous somatostatin has been shown to be as effective as ergotamine in the short-term treatment of
Octreotide vs prochlorperazine—migraine headache treatment cluster headache, and recently, interest in its use for cluster and migraine headaches has emerged [11]. Octreotide (OC) is a synthetic somatostatin analog with a longer half-life than native somatostatin [12]. The analgesic effect of OC with headaches associated with growth hormone-secreting tumor has been established [13]; however, its effects on migrainetype headaches have not been thoroughly investigated. The ideal medication for treating headaches would have quick onset of action, few side effects, high efficacy, low rate of headache recurrence, and low potential for dependence. If octreotide were found to cause few side effects and to have similar efficacy to that of standard therapy with antidopaminergic drugs, it could become a first-line therapy for migraines in the ED.
1.2. Goals of this investigation Our goals were to evaluate the efficacy of intravenous OC for the treatment of migraines, when compared to standard therapy with PC.
161 Table 1
Migraine criteria used for patient enrollment
Migraine with aura
Migraine without aura
At least 2 attacks fulfilling the below characteristics Headache has at least 3 of the following 4 characteristics: 1. One or more fully reversible aura symptoms indicating focal cerebral cortical and/or brain stem dysfunction 2. At least one aura symptom develops gradually for N4 min or 2 or more symptoms occur in succession 3. No aura symptom lasts more than 60 min; if more than one aura symptom is present, accepted duration is proportionally increased 4. Headache follows aura with a free interval of b60 min (it may also begin before or simultaneously with the aura)
At least 5 attacks fulfilling the below characteristics Headache attacks lasting 4-72 h (untreated or unsuccessfully treated) Headache has at least 2 of the following 4 characteristics: 1. Unilateral location 2. Pulsating quality 3. Moderate or severe intensity that inhibits or prohibits daily activities 4. Aggravated by walking stairs or similar routine physical activity During headache at least 1 of the 2 following symptoms occur: 1. Nausea and/or vomiting 2. Photophobia and phonophobia
2. Methods 2.1. Study design
2.4. Interventions
The study was conducted as a double-blinded, randomized controlled trial. This study was approved by the institutional review board of the hosting institution and was registered with www.clinicaltrials.gov before patient enrollment. Written informed consent was obtained from all participants. No conflicts of interest were noted.
On the basis of a computer-generated randomization table, each subject received either 100 μg octreotide or 10 mg of prochlorperazine intravenously for a 2-minute period. Study participants and investigators were blinded to the medication used in each case.
2.2. Setting The study was conducted in an academic, suburban, community hospital ED, with annual census of approximately 65 000 patient visits.
2.3. Selection of participants Participants were enrolled as a convenience sample; all eligible patients were approached, when an investigator was available. Adults between the ages of 18 and 65 years, who met International Headache Society criteria for migraine with or without aura and with at least one prior episode of a similar headache, were eligible for enrollment (see Table 1) [14]. Exclusion criteria included pregnancy and lactation, premedication within 6 hours of being enrolled in the study, more than 6 prior headaches per month, allergy to study drugs, nonmigraine headache, substance abuse, alcohol abuse, diabetes mellitus, or any coexisting medical condition that might expose the patients to a disproportionately increased risk of a significant adverse event from the study drugs.
2.5. Methods of measurement After informed consent and evaluation for inclusion and exclusion criteria, patients were asked to grade nausea, pain, and sedation, each on a 10-cm visual analog scale (VAS). At 60 minutes poststudy injection, each patient was asked to again grade nausea, pain, and sedation on a separate set of 10-cm VAS, without viewing the initial scores, and to write whether he or she was satisfied with the results of the treatment, as a “yes” or “no” answer. Clinically successful treatment was defined as achievement of the following: patient satisfaction with treatment and either a decrease of 50% or more in the pain score when compared with the initial score or an absolute pain score of 2.5 cm or less. Failure to achieve these criteria constituted treatment failure. The study was concluded at 60 minutes postinjection at which time the treating physician offered an appropriate rescue medication. The treating physician monitored each patient for the occurrence of side effects and asked each if he or she felt “restless” at the time of posttreatment assessment, as a simple measure of akathisia. Each patient was then contacted by telephone approximately 48 hours after discharge to determine the early relapse rate.
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2.6. Data collection and processing
Table 3
Data for each patient were collected on a standardized set of forms and were later entered into a Microsoft Office Excel 2003-SP2 spreadsheet (Microsoft Corp, Redmond, Wash) for analysis.
2.7. Outcome measures The primary outcome was clinical success, as defined above. Secondary outcomes included change in pain scale, change in nausea scale, change in sedation scale, and occurrence of any side effects, and specifically restlessness consistent with akathisia.
2.8. Data analysis Statistical probabilities of differences in mean continuous scales were compared by unpaired Student t tests. Nominal data were compared using χ2 tests. All calculations were performed in Microsoft Excel.
3. Results
Postintervention data
Postmedication data (Count [%], mean ± SD, or mean [95% confidence interval])
P
Characteristic
Prochlorperazine
Octreotide
N Pain (mm) Δ pain (mm)
20 20.8 ± 21.1 −50.5 (−41.5, −59.4) 9.2 ± 15.5 −36.6 (−24.7, −48.6) 42.5 ± 33.2 19.7 (3.5, 35.9) 2 (10)
23 43.2 ± 30.4 −33.3 (−21.3, −45.2) 20.0 ± 28.0 −27.3 (−17.2, −37.4) 23.8 ± 24.5 −2.7 (−12.9, 7.6) 11 (48)
b.01
2 (10) 18 (90) 7 (35)
6 (26) 13 (57) 2 (9)
.10 b.01 b.01
Nausea (mm) Δ nausea (mm) Sedation (mm) Δ sedation (mm) Required rescue medication Recurrence b48 h Treatment success Akathisia
.01 .03 .12 .26 .04 .03
primary care physician, or having a seen a neurologist for migraines. Similarly, the groups were not statistically different with respect to pretreatment status, comprising pain, nausea, or sedation on the VAS. These data are presented in Table 2.
3.1. Characteristics of study subjects Between February 2006 and February 2007, of the 53 patients identified, 44 gave written consent; 20 patients were randomized to receive prochlorperazine and 24 to receive octreotide. Eight patients were excluded because of recent medication use. One patient elected not to participate after reviewing the study information with an investigator. One patient in the octreotide group failed to complete the protocol after receiving octreotide and experiencing some mild facial flushing and bradycardia that resolved without treatment. The prochlorperazine and octreotide groups were not statistically different in composition in sex, having a Table 2 Patient demographic characteristics and pretreatment scores for each study group Baseline data (Mean ± SD or Count [%])
P
Characteristic
Prochlorperazine
Octreotide
N Age (y) Sex Male Female Have primary care Have neurologist Pain (mm) Nausea (mm) Sedation (mm)
20 27.5 ± 5.8
24 31.1 ± 11.1
6 (30) 14 (70) 14 (70) 7 (35) 71.6 ± 15.3 45.9 ± 26.1 24.2 ± 27.2
5 (22) 19 (78) 17 (74) 9 (39) 75.4 ± 17.7 45.4 ± 29.3 25.3 ± 24.4
.17
3.2. Main results Comparison of the change in median VAS scores for 60 minutes demonstrated that octreotide was less effective at reducing pain (P = .03) and producing clinical success (P b .01). Median improvements in VAS pain scores were 50.5 mm for prochlorperazine vs 33.3 mm for octreotide. Median VAS improvement in nausea scores were 36.6 mm for prochlorperazine and 27.3 mm for octreotide (P = .26). Sedation was increased by a mean of 19.7 mm in the prochlorperazine group and decreased by 2.7 mm in the octreotide group (P = .03). Restlessness consistent with akathisia was noted by 35% of the PC group and 8% of the OC group (P b .01). At 60 minutes, rescue medication was required by 48% of the patients in the octreotide group, whereas 10% of the prochlorperazine group required such therapy (P b .01). All 44 patients were contacted for followup at 48 to 72 hours after enrollment. At that time, 10% of the prochlorperazine and 25% of the octreotide patients had experienced some headache recurrence (P = .1). Posttreatment data are presented in Table 3.
.22 .41 .40 .44 .95 .88
3.3. Limitations Our study methodology had several limitations. Our sample size was small, but because of the relatively large magnitude of the clinical effects studied, our findings were
Octreotide vs prochlorperazine—migraine headache treatment statistically significant. However, our confidence intervals for the average effects are relatively wide, interjecting uncertainty into the decision as to whether the effects would actually be clinically significant. At the time of planned interim analysis, it was decided that the difference between the groups was significant enough to warrant conclusion of this study. Other study designs similar to ours have used estimates of 18 patients per group for detection of clinically significant differences in pain scores of 25 mm, assuming an α value of .05, a power of 0.80, and an SD of 26.5 mm [5]. The use of convenience sampling detracts somewhat from the true random quality of the enrollment process but was used to involve a smaller, more informed, and committed group of investigators. In addition, a disproportionate percentage of patients noted restlessness in the PC group compared to the OC group (35% vs 8%; P b .01). It is likely that this restlessness in many cases represented akathisia and may contribute to a patient possibly stating they are satisfied with a treatment in an effort to leave the treating facility. However, our use of a composite end point for treatment success (both an affirmative statement that they were satisfied and VAS improvement) makes this unlikely to be a large contributor to the differences found within our study. Finally, the fairly strict definition of migraine headaches is likely used infrequently by practicing clinical emergency physicians. It is conceivable that either study medication might be more or less beneficial for patients with less typical “migraine headaches” often seen clinically in the ED, but not included in this study.
4. Discussion Our results demonstrate a superiority of PC over OC in treatment of headaches meeting the definition of migraines according to the International Heachache Society criteria. Somatostatin is known to have an inhibitory effect on a number of neuropetides, inhibits serotonin, bradykinin, prostaglandins, substance P, and vasoactive intestinal peptide, all which have been implicated in migraine [15-17]. Native somatostatin is an unstable compound and is broken down in minutes. However, octreotide, a somatostatin analog, has a longer half-life [12]. Intravenous somatostatin has been shown to be as effective as ergotamine in the short-term treatment of cluster headache [11]. Five somatostatin receptors have been cloned with octreotide acting predominantly on sst2 and sst5. The distribution of sst2 within the central nervous system strongly suggests that this particular somatostatin receptor has a role in cranial nociception, being highly expressed in the trigeminal nucleus caudalis and periaqueductal gray [17]. Kapicioglu et al [18] performed a double-blind study comparing subcutaneous octreotide to placebo in treating migraine. They found there to be a significantly greater relief of pain with octreotide at 2 and 6 hours compared to
163
placebo (76% vs 25%; P b .02) and noted that 47% of those in the octreotide group had complete relief compared to no patients in the placebo group. They went on to note that those patients in the octreotide group had earlier relief of symptoms and no side effects. The only minor adverse event related to the administration of octreotide was a local reaction in 3 patients (18%). This paucity of serious adverse effects is further demonstrated by a study performed recently in Netherlands comparing the effects of large doses of somatostatin analogs used in the treatment of acromegaly, no clinically relevant changes in vital signs, routine chemistry, and urinalysis were observed with octreotide use. Electrocardiogram analyses showed no newly occurring or worsening of known cardiac abnormalities 2 and 24 hours after injection with octreotide [19]. Levy et al [20] also compared octreotide to placebo in a double-blinded study but found no difference. However, this study had significant limitations, in that the patients treated themselves at home with an injection of either placebo or octreotide for 2 episodes of headache and recorded their level of pain relief at 2 hours. Furthermore, this study also used subcutaneous injection of octreotide rather than intravenous injection. Matharu et al [21] also performed a double-blind study comparing subcutaneous octreotide to placebo but investigated cluster headaches rather than migraines. They found there to be a significant improvement with the use of octreotide over placebo (52% vs 36%). To our knowledge, our study is the first to test ED use of intravenous octreotide for clearly defined migraine headaches. We theorized that the use of intravenous rather than subcutaneous octreotide would allow for establishment of a more rapid and profound effect of the medication not previously realized in other studies. We further hypothesized that OC would demonstrate noninferiority when compared to PC. Although our study did show success rates (54.5%) not unlike those found in these previous placebo controlled studies, the treatment success as rated by patients giving both a yes/no answer and using a VAS was inferior in comparison with prochlorperazine. Side effect rates were higher in the PC group, but all of these effects were noted to be consistent with akathisia and similar to the PC-related akathisia rates noted by Drotts and Vinson [10] in a previous study. These rates of akathisia coupled with the significantly higher level of posttreatment sedation are 2 characteristics that might lead a clinician to use alternative medications. Octreotide has shown some promise for the treatment of other headache subtypes, but our study does not merit use as a first-line or second-line agent in the treatment of migraine headaches.
5. Conclusion Prochlorperazine was statistically superior to octreotide in clinical success rate and decrease in pain in migraine patients but caused more restlessness and sedation.
164
Acknowledgment The authors would like to acknowledge the support of the pharmacy staff at Darnall, especially Mr. Adam Alvarez. Dr Paresh Patel and Dr. Sean Fortson also assisted in the conception and preparation of this research.
References [1] Goldstein JN, Camargo Jr CA, Pelletier AJ, Edlow JA. Headache in United States emergency departments: demographics, work-up and frequency of pathological diagnoses. Cephalalgia 2006;26(6):684-90. [2] Vinson DR. Treatment patterns of isolated benign headache in US emergency departments. Ann Emerg Med 2002;39(3):215-22. [3] De Carli GF, Fabbri L, Cavazzuti L, Roncolato M, Agnello V, Recchia G. The epidemiology of migraine: a retrospective study in Italian emergency departments. Headache 1998;38(9):697-704. [4] Callaham M, Raskin N. A controlled study of dihydroergotamine in the treatment of acute migraine headache. Headache 1986;26(4): 168-71. [5] Tanen DA, Miller S, French T, Riffenburgh RH. Intravenous sodium valproate versus prochlorperazine for the emergency department treatment of acute migraine headaches: a prospective, randomized, double-blind trial. Ann Emerg Med 2003;41(6):847-53. [6] Shrestha M, Singh R, Moreden J, Hayes JE. Ketorolac vs. chlorpromazine in the treatment of acute migraine without aura. A prospective, randomized, double-blind trial. Arch Intern Med 1996; 156(15):1725-8. [7] Brousseau DC, Duffy SJ, Anderson AC, Linakis JG. Treatment of pediatric migraine headaches: a randomized, double-blind trial of prochlorperazine versus ketorolac. Ann Emerg Med 2004;43(2):256-62. [8] Miner JR, Fish SJ, Smith SW, Biros MH. Droperidol vs. prochlorperazine for benign headaches in the emergency department. Acad Emerg Med 2001;8(9):873-9.
M.A. Miller et al. [9] Weaver CS, Jones JB, Chisholm CD, Foley MJ, Giles BK, Somerville GG, et al. Droperidol vs. prochlorperazine for the treatment of acute headache. J Emerg Med 2004;26(2):145-50. [10] Drotts DL, Vinson DR. Prochlorperazine induces akathisia in emergency patients. Ann Emerg Med 1999;34(4 Pt 1):469-75. [11] Sicuteri F, Geppetti P, Marabini S, Lembeck F. Pain relief by somatostatin in attacks of cluster headache. Pain 1984;18(4): 359-65. [12] Harris AG. Somatostatin and somatostatin analogues: pharmacokinetics and pharmacodynamic effects. Gut 1994;35(3 Suppl):S1-4. [13] Sassolas G. The role of Sandostatin in acromegaly. Metabolism 1992; 41(9 Suppl 2):39-43. [14] Classification Committee of the International Headache Society. Classification and diagnosis criteria for headache disorders, cranial neuralgias and facial pain. Cephalagia 1988;8(Suppl 7):1-96. [15] Recht LD, Abrams GM. Neuropeptides and their role in nociception and analgesia. Neurol Clin 1986;4(4):833-52. [16] Sagar SM, Beal MF, Marshall PE, Landis DM, Martin JB. Implications of neuropeptides in neurological diseases. Peptides 1984;5(Suppl 1): 255-62. [17] Samsam M, Covenas R, Yajeya J, Ahangari R, Narvaez JA, Montes-Gonzalo MC, et al. Implication of the neuropeptides methionine enkephalin, neurotensin and somatostatin of the caudal trigeminal nucleus in the experimental migraine. Rev Neurol 2002; 34(8):724-9. [18] Kapicioglu S, Gokce E, Kapicioglu Z, Ovali E. Treatment of migraine attacks with a long-acting somatostatin analogue (octreotide, SMS 201-995). Cephalalgia 1997;17(1):27-30. [19] Hoek JVD, et al. A single-dose comparison of the acute effects between the new somatostatin analog SOM230 and octreotide in acromegalic patients. J Clin Endocrinol Metab 2004;89(2): 638-45. [20] Levy MJ, Matharu MS, Bhola R, Meeran K, Goadsby PJ. Octreotide is not effective in the acute treatment of migraine. Cephalalgia 2005;25 (1):48-55. [21] Matharu MS, Levy MJ, Meeran K, Goadsby PJ. Subcutaneous octreotide in cluster headache: randomized placebo-controlled doubleblind crossover study. Ann Neurol 2004;56(4):488-94.
www.elsevier.com/locate/ajem
Original Contribution
Randomized evaluation of octreotide vs prochlorperazine for ED treatment of migraine headache☆ Michael A. Miller MD a,⁎, Marc E. Levsky MD b , William Enslow DO a , Alex Rosin MD b a
Department of Emergency Medicine, Tripler Army Medical Center, Honolulu Hawaii, 96859, USA Department of Emergency Medicine, Carl R. Darnall Army Medical Center, Ft Hood, TX 76544, USA
b
Received 5 November 2007; revised 24 December 2007; accepted 22 January 2008
Abstract Patients with headaches account for approximately 2% of all ED visits, with migraines being the most common defined primary headache syndrome. Our goals were to evaluate the efficacy of intravenous octreotide (OC) for the treatment of migraines, when compared to standard therapy with prochlorperazine. Methods: The study was conducted as a double-blinded, randomized controlled trial. Each subject received either 100 μg of octreotide or 10 mg of prochlorperazine intravenously for a 2-minute period. Results: Comparison of the change in median visual analog scale scores for 60 minutes demonstrated that octreotide was less effective at reducing pain (P = .03) and producing clinical success (P b .01). Restlessness consistent with akathisia was noted by 35% of the PC group and 8% of the OC group (P b .01). At 60 minutes, rescue medication was required by 48% of the patients in the OC group, whereas 10% of the PC group required such therapy (P b .01). All 44 patients were contacted for follow-up at 48 to 72 hours after enrollment. At that time, 10% of the prochlorperazine and 25% of the octreotide patients had experienced some headache recurrence (P = .1). Conclusion: Prochlorperazine was statistically superior to octreotide in clinical success rate and decrease in pain in migraine patients but caused more restlessness and sedation. © 2009 Published by Elsevier Inc.
1. Introduction 1.1. Background Patients with headaches account for approximately 2% of all emergency department (ED) visits, with migraines being the most common defined primary headache syndrome [1-3]. Patients presenting to the ED often have failed outpatient Presented at the ACEP Scientific Assembly, Seattle, WA, October 2007. ☆ This work is the opinion of the authors and does not necessarily represent the opinion of the U.S. Army or the Department of Defense. ⁎ Corresponding author. Tel.: +1 254 288 8303; fax: +1 254 286 7055. E-mail address: [email protected] (M.A. Miller). 0735-6757/$ – see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.ajem.2008.01.015
therapy and exhibit severe and persistent symptoms. Treatment options have expanded, but patients are still often met with the frustrating failures of pharmaceutical intervention. In 1986, a nonopioid, prochlorperazine (PC), was noted serendipitously to relieve acute migraine headache pain [4]. Prochlorperazine has been successfully used to treat migraine headaches for the past several decades and has been accepted as a first-line treatment of headaches in many EDs often used as a comparative group for clinical trials comparing pharmaceutical efficacy [1,5-9]. Unfortunately, PC frequently causes side effects including dysphoria, drowsiness, akathisia, and extrapyramidal effects [5,8,10]. In the past, intravenous somatostatin has been shown to be as effective as ergotamine in the short-term treatment of
Octreotide vs prochlorperazine—migraine headache treatment cluster headache, and recently, interest in its use for cluster and migraine headaches has emerged [11]. Octreotide (OC) is a synthetic somatostatin analog with a longer half-life than native somatostatin [12]. The analgesic effect of OC with headaches associated with growth hormone-secreting tumor has been established [13]; however, its effects on migrainetype headaches have not been thoroughly investigated. The ideal medication for treating headaches would have quick onset of action, few side effects, high efficacy, low rate of headache recurrence, and low potential for dependence. If octreotide were found to cause few side effects and to have similar efficacy to that of standard therapy with antidopaminergic drugs, it could become a first-line therapy for migraines in the ED.
1.2. Goals of this investigation Our goals were to evaluate the efficacy of intravenous OC for the treatment of migraines, when compared to standard therapy with PC.
161 Table 1
Migraine criteria used for patient enrollment
Migraine with aura
Migraine without aura
At least 2 attacks fulfilling the below characteristics Headache has at least 3 of the following 4 characteristics: 1. One or more fully reversible aura symptoms indicating focal cerebral cortical and/or brain stem dysfunction 2. At least one aura symptom develops gradually for N4 min or 2 or more symptoms occur in succession 3. No aura symptom lasts more than 60 min; if more than one aura symptom is present, accepted duration is proportionally increased 4. Headache follows aura with a free interval of b60 min (it may also begin before or simultaneously with the aura)
At least 5 attacks fulfilling the below characteristics Headache attacks lasting 4-72 h (untreated or unsuccessfully treated) Headache has at least 2 of the following 4 characteristics: 1. Unilateral location 2. Pulsating quality 3. Moderate or severe intensity that inhibits or prohibits daily activities 4. Aggravated by walking stairs or similar routine physical activity During headache at least 1 of the 2 following symptoms occur: 1. Nausea and/or vomiting 2. Photophobia and phonophobia
2. Methods 2.1. Study design
2.4. Interventions
The study was conducted as a double-blinded, randomized controlled trial. This study was approved by the institutional review board of the hosting institution and was registered with www.clinicaltrials.gov before patient enrollment. Written informed consent was obtained from all participants. No conflicts of interest were noted.
On the basis of a computer-generated randomization table, each subject received either 100 μg octreotide or 10 mg of prochlorperazine intravenously for a 2-minute period. Study participants and investigators were blinded to the medication used in each case.
2.2. Setting The study was conducted in an academic, suburban, community hospital ED, with annual census of approximately 65 000 patient visits.
2.3. Selection of participants Participants were enrolled as a convenience sample; all eligible patients were approached, when an investigator was available. Adults between the ages of 18 and 65 years, who met International Headache Society criteria for migraine with or without aura and with at least one prior episode of a similar headache, were eligible for enrollment (see Table 1) [14]. Exclusion criteria included pregnancy and lactation, premedication within 6 hours of being enrolled in the study, more than 6 prior headaches per month, allergy to study drugs, nonmigraine headache, substance abuse, alcohol abuse, diabetes mellitus, or any coexisting medical condition that might expose the patients to a disproportionately increased risk of a significant adverse event from the study drugs.
2.5. Methods of measurement After informed consent and evaluation for inclusion and exclusion criteria, patients were asked to grade nausea, pain, and sedation, each on a 10-cm visual analog scale (VAS). At 60 minutes poststudy injection, each patient was asked to again grade nausea, pain, and sedation on a separate set of 10-cm VAS, without viewing the initial scores, and to write whether he or she was satisfied with the results of the treatment, as a “yes” or “no” answer. Clinically successful treatment was defined as achievement of the following: patient satisfaction with treatment and either a decrease of 50% or more in the pain score when compared with the initial score or an absolute pain score of 2.5 cm or less. Failure to achieve these criteria constituted treatment failure. The study was concluded at 60 minutes postinjection at which time the treating physician offered an appropriate rescue medication. The treating physician monitored each patient for the occurrence of side effects and asked each if he or she felt “restless” at the time of posttreatment assessment, as a simple measure of akathisia. Each patient was then contacted by telephone approximately 48 hours after discharge to determine the early relapse rate.
162
M.A. Miller et al.
2.6. Data collection and processing
Table 3
Data for each patient were collected on a standardized set of forms and were later entered into a Microsoft Office Excel 2003-SP2 spreadsheet (Microsoft Corp, Redmond, Wash) for analysis.
2.7. Outcome measures The primary outcome was clinical success, as defined above. Secondary outcomes included change in pain scale, change in nausea scale, change in sedation scale, and occurrence of any side effects, and specifically restlessness consistent with akathisia.
2.8. Data analysis Statistical probabilities of differences in mean continuous scales were compared by unpaired Student t tests. Nominal data were compared using χ2 tests. All calculations were performed in Microsoft Excel.
3. Results
Postintervention data
Postmedication data (Count [%], mean ± SD, or mean [95% confidence interval])
P
Characteristic
Prochlorperazine
Octreotide
N Pain (mm) Δ pain (mm)
20 20.8 ± 21.1 −50.5 (−41.5, −59.4) 9.2 ± 15.5 −36.6 (−24.7, −48.6) 42.5 ± 33.2 19.7 (3.5, 35.9) 2 (10)
23 43.2 ± 30.4 −33.3 (−21.3, −45.2) 20.0 ± 28.0 −27.3 (−17.2, −37.4) 23.8 ± 24.5 −2.7 (−12.9, 7.6) 11 (48)
b.01
2 (10) 18 (90) 7 (35)
6 (26) 13 (57) 2 (9)
.10 b.01 b.01
Nausea (mm) Δ nausea (mm) Sedation (mm) Δ sedation (mm) Required rescue medication Recurrence b48 h Treatment success Akathisia
.01 .03 .12 .26 .04 .03
primary care physician, or having a seen a neurologist for migraines. Similarly, the groups were not statistically different with respect to pretreatment status, comprising pain, nausea, or sedation on the VAS. These data are presented in Table 2.
3.1. Characteristics of study subjects Between February 2006 and February 2007, of the 53 patients identified, 44 gave written consent; 20 patients were randomized to receive prochlorperazine and 24 to receive octreotide. Eight patients were excluded because of recent medication use. One patient elected not to participate after reviewing the study information with an investigator. One patient in the octreotide group failed to complete the protocol after receiving octreotide and experiencing some mild facial flushing and bradycardia that resolved without treatment. The prochlorperazine and octreotide groups were not statistically different in composition in sex, having a Table 2 Patient demographic characteristics and pretreatment scores for each study group Baseline data (Mean ± SD or Count [%])
P
Characteristic
Prochlorperazine
Octreotide
N Age (y) Sex Male Female Have primary care Have neurologist Pain (mm) Nausea (mm) Sedation (mm)
20 27.5 ± 5.8
24 31.1 ± 11.1
6 (30) 14 (70) 14 (70) 7 (35) 71.6 ± 15.3 45.9 ± 26.1 24.2 ± 27.2
5 (22) 19 (78) 17 (74) 9 (39) 75.4 ± 17.7 45.4 ± 29.3 25.3 ± 24.4
.17
3.2. Main results Comparison of the change in median VAS scores for 60 minutes demonstrated that octreotide was less effective at reducing pain (P = .03) and producing clinical success (P b .01). Median improvements in VAS pain scores were 50.5 mm for prochlorperazine vs 33.3 mm for octreotide. Median VAS improvement in nausea scores were 36.6 mm for prochlorperazine and 27.3 mm for octreotide (P = .26). Sedation was increased by a mean of 19.7 mm in the prochlorperazine group and decreased by 2.7 mm in the octreotide group (P = .03). Restlessness consistent with akathisia was noted by 35% of the PC group and 8% of the OC group (P b .01). At 60 minutes, rescue medication was required by 48% of the patients in the octreotide group, whereas 10% of the prochlorperazine group required such therapy (P b .01). All 44 patients were contacted for followup at 48 to 72 hours after enrollment. At that time, 10% of the prochlorperazine and 25% of the octreotide patients had experienced some headache recurrence (P = .1). Posttreatment data are presented in Table 3.
.22 .41 .40 .44 .95 .88
3.3. Limitations Our study methodology had several limitations. Our sample size was small, but because of the relatively large magnitude of the clinical effects studied, our findings were
Octreotide vs prochlorperazine—migraine headache treatment statistically significant. However, our confidence intervals for the average effects are relatively wide, interjecting uncertainty into the decision as to whether the effects would actually be clinically significant. At the time of planned interim analysis, it was decided that the difference between the groups was significant enough to warrant conclusion of this study. Other study designs similar to ours have used estimates of 18 patients per group for detection of clinically significant differences in pain scores of 25 mm, assuming an α value of .05, a power of 0.80, and an SD of 26.5 mm [5]. The use of convenience sampling detracts somewhat from the true random quality of the enrollment process but was used to involve a smaller, more informed, and committed group of investigators. In addition, a disproportionate percentage of patients noted restlessness in the PC group compared to the OC group (35% vs 8%; P b .01). It is likely that this restlessness in many cases represented akathisia and may contribute to a patient possibly stating they are satisfied with a treatment in an effort to leave the treating facility. However, our use of a composite end point for treatment success (both an affirmative statement that they were satisfied and VAS improvement) makes this unlikely to be a large contributor to the differences found within our study. Finally, the fairly strict definition of migraine headaches is likely used infrequently by practicing clinical emergency physicians. It is conceivable that either study medication might be more or less beneficial for patients with less typical “migraine headaches” often seen clinically in the ED, but not included in this study.
4. Discussion Our results demonstrate a superiority of PC over OC in treatment of headaches meeting the definition of migraines according to the International Heachache Society criteria. Somatostatin is known to have an inhibitory effect on a number of neuropetides, inhibits serotonin, bradykinin, prostaglandins, substance P, and vasoactive intestinal peptide, all which have been implicated in migraine [15-17]. Native somatostatin is an unstable compound and is broken down in minutes. However, octreotide, a somatostatin analog, has a longer half-life [12]. Intravenous somatostatin has been shown to be as effective as ergotamine in the short-term treatment of cluster headache [11]. Five somatostatin receptors have been cloned with octreotide acting predominantly on sst2 and sst5. The distribution of sst2 within the central nervous system strongly suggests that this particular somatostatin receptor has a role in cranial nociception, being highly expressed in the trigeminal nucleus caudalis and periaqueductal gray [17]. Kapicioglu et al [18] performed a double-blind study comparing subcutaneous octreotide to placebo in treating migraine. They found there to be a significantly greater relief of pain with octreotide at 2 and 6 hours compared to
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placebo (76% vs 25%; P b .02) and noted that 47% of those in the octreotide group had complete relief compared to no patients in the placebo group. They went on to note that those patients in the octreotide group had earlier relief of symptoms and no side effects. The only minor adverse event related to the administration of octreotide was a local reaction in 3 patients (18%). This paucity of serious adverse effects is further demonstrated by a study performed recently in Netherlands comparing the effects of large doses of somatostatin analogs used in the treatment of acromegaly, no clinically relevant changes in vital signs, routine chemistry, and urinalysis were observed with octreotide use. Electrocardiogram analyses showed no newly occurring or worsening of known cardiac abnormalities 2 and 24 hours after injection with octreotide [19]. Levy et al [20] also compared octreotide to placebo in a double-blinded study but found no difference. However, this study had significant limitations, in that the patients treated themselves at home with an injection of either placebo or octreotide for 2 episodes of headache and recorded their level of pain relief at 2 hours. Furthermore, this study also used subcutaneous injection of octreotide rather than intravenous injection. Matharu et al [21] also performed a double-blind study comparing subcutaneous octreotide to placebo but investigated cluster headaches rather than migraines. They found there to be a significant improvement with the use of octreotide over placebo (52% vs 36%). To our knowledge, our study is the first to test ED use of intravenous octreotide for clearly defined migraine headaches. We theorized that the use of intravenous rather than subcutaneous octreotide would allow for establishment of a more rapid and profound effect of the medication not previously realized in other studies. We further hypothesized that OC would demonstrate noninferiority when compared to PC. Although our study did show success rates (54.5%) not unlike those found in these previous placebo controlled studies, the treatment success as rated by patients giving both a yes/no answer and using a VAS was inferior in comparison with prochlorperazine. Side effect rates were higher in the PC group, but all of these effects were noted to be consistent with akathisia and similar to the PC-related akathisia rates noted by Drotts and Vinson [10] in a previous study. These rates of akathisia coupled with the significantly higher level of posttreatment sedation are 2 characteristics that might lead a clinician to use alternative medications. Octreotide has shown some promise for the treatment of other headache subtypes, but our study does not merit use as a first-line or second-line agent in the treatment of migraine headaches.
5. Conclusion Prochlorperazine was statistically superior to octreotide in clinical success rate and decrease in pain in migraine patients but caused more restlessness and sedation.
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Acknowledgment The authors would like to acknowledge the support of the pharmacy staff at Darnall, especially Mr. Adam Alvarez. Dr Paresh Patel and Dr. Sean Fortson also assisted in the conception and preparation of this research.
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