Intramuscular tramadol vs. diclofenac sodium for the treatment of acute migraine attacks in emergency department: a prospective, randomised, double-blind study

Abstract

The aim of this prospective, randomised, double-blind study was to evaluate the efficacy of intramuscular (IM) tramadol 100 mg in emergency department treatment of acute migraine attack and to compare it with that of IM diclofenac sodium 75 mg. Forty patients who were admitted to our emergency department with acute migraine attack according to the International Headache Society criteria were included in the study. Patients were randomised to receive either tramadol 100 mg ( n =20) or diclofenac sodium 75 mg ( n =20) intramuscularly. Patients rated their pain on a four-point verbal scale (0=none, 1=mild, 2=moderate, 3=severe) at the beginning of the trial and at 30, 60, 90 and 120 min. At each time interval, severity of associated symptoms were also questioned and recorded. Global evaluation of the drugs by patients and doctors were also recorded. Patients were also asked if they would prefer the same injection in future visits. Any adverse events, whether related to the drug or not, were also recorded. Patients were followed up by telephone 48 h later to check for any headache recurrence. Two-hour pain response rate, which was the primary endpoint, was 80% for both tramadol and diclofenac groups. There were no statistically significant differences among groups in terms of 48-h pain response, rescue treatment, associated symptoms' response, headache recurrence and adverse event rates. Fifteen (75%) patients in the tramadol group and 16 (80%) patients in the diclofenac group stated that they may prefer the same agent for future admissions. In selected patients, tramadol 100 mg IM may be an effective and reliable alternative treatment choice in acute migraine attacks. [PUBLICATION ABSTRACT]

J Headache Pain (2005) 6:143148

DOI 10.1007/s10194-005-0169-yORIGINALZulfi Engindeniz

Celaleddin Demircan

Necdet Karli

Erol Armagan

Mehtap Bulut

Tayfun Aydin

Mehmet ZarifogluIntramuscular tramadol vs. diclofenac sodium

for the treatment of acute migraine attacks

in emergency department: a prospective,

randomised, double-blind studyReceived: 6 February 2005

Accepted in revised form: 15 April 2005

Published online: 13 May 2005Z. Engindeniz () E. Armagan M. BulutT. AydinDepartment of Emergency Medicine,

Uludag University Medical Faculty,

Acil Tip ABD Gorukle,

Bursa 16059, Turkey

e-mail: [email protected]

Tel.: [phone]

Fax: [phone]C. DemircanDepartment of Internal Medicine,

Uludag University Medical Faculty,

Bursa, TurkeyN. Karli M. ZarifogluDepartment of Neurology,

Uludag University Medical Faculty,

Bursa, TurkeyAbstract The aim of this prospective, randomised, double-blind study

was to evaluate the efficacy of intramuscular (IM) tramadol 100 mg in

emergency department treatment of

acute migraine attack and to compare it with that of IM diclofenac

sodium 75 mg. Forty patients who

were admitted to our emergency

department with acute migraine

attack according to the International

Headache Society criteria were

included in the study. Patients were

randomised to receive either tramadol 100 mg (n=20) or diclofenac

sodium 75 mg (n=20) intramuscularly. Patients rated their pain on a

four-point verbal scale (0=none,

1=mild, 2=moderate, 3=severe) at

the beginning of the trial and at 30,

60, 90 and 120 min. At each time

interval, severity of associated

symptoms were also questioned and

recorded. Global evaluation of the

drugs by patients and doctors were

also recorded. Patients were also

asked if they would prefer the same

injection in future visits. Any

adverse events, whether related to

the drug or not, were also recorded.

Patients were followed up by telephone 48 h later to check for any

headache recurrence. Two-hour pain

response rate, which was the primary endpoint, was 80% for both tramadol and diclofenac groups. There

were no statistically significant differences among groups in terms of

48-h pain response, rescue treatment, associated symptoms

response, headache recurrence and

adverse event rates. Fifteen (75%)

patients in the tramadol group and

16 (80%) patients in the diclofenac

group stated that they may prefer the

same agent for future admissions. In

selected patients, tramadol 100 mg

IM may be an effective and reliable

alternative treatment choice in acute

migraine attacks.Key words Migraine treatment

Tramadol Diclofenac

Randomised controlled trialIntroductionMigraine headache is a common presenting complaint to

the emergency department (ED). Aims of treatment

include rapid pain relief, improvement in associatedsymptoms, minimisation of length of stay and prevention

of recurrence. Many treatment alternatives have been

shown to be effective in the treatment of acute migraine

attack including non-steroidal anti-inflammatory drugs

(NSAID), antiemetics, phenothiazines, narcotics, ergot

alkaloids and triptans [19].144Although it is not the recommended first-line therapy,

in nearly half of migraine headaches emergency physicians in the USA prefer parenteral opioids [10]. Tramadol

is an opioid agent with central activity. Mechanism of its

analgesic activity involves two components: low-affinity

binding to opioid receptors and inhibition of monoamine

reuptake [11]. Tramadol has a proven analgesic activity

for many acute and chronic pain conditions [1216].

Adverse effects, nausea in particular, are dose-dependent

and therefore considerably more likely to appear if the

loading dose is high. Other adverse effects are similar to

those of other opioids but they appear to be less severe[11]. Potential dependence, tolerance and abuse rates of

tramadol are also reported to be relatively low [17]. With

these features tramadol appears to have a potential role in

the treatment of headaches. However, there is limited data

on its use in headache [10, 18] and we could not find any

study on its use in acute migraine attack.The aim of this study was to evaluate the efficacy of

intramuscular (IM) tramadol 100 mg in ED treatment of

acute migraine attack and to compare it with that of IM

diclofenac sodium 75 mg, an agent shown to be effective

in treatment of acute migraine attacks [14], in a prospective, randomised and double-blind fashion. The primary

outcome measure of the study was 2-h pain response after

the injection of the study drug. A sample size of 32

patients was determined to achieve 80% power to detect

an effect size of 0.5 using a 1 degree of freedom Chi-

Square Test with a significance level (alpha) of 0.05.MethodsThis prospective, randomised, double-blind trial was conducted

in a university hospital ED with an annual census of about

26 000. The study was designed according to the second edition

of guidelines for controlled trials of drugs in migraine [19]. The

institutional review board and ethics committee approved the

study (Decision number: 2003-24-03). Informed consent of all

eligible patients was obtained before the study. The study was

performed in accordance with the ethical standards of the 1964

Declaration of Helsinki.All patients between 18 and 65 years of age with acute

migraine attack according to the second edition of the

International Headache Society (IHS) criteria for migraine without aura [20] were eligible. Patients with any known sensitivity

to either tramadol or diclofenac, patients taking excessive analgesics (more than 10 days per month), patients using antidepressants and antipsychotics regularly within the last 3 months,

patients with history of epilepsy, alcohol or drug abuse, patients

over 50 years of age with new onset migraine and pregnant or

lactating patients were excluded from the study.Patients with other types of headache (e.g., tension-type

headache) together with migraine were included in the study if

they could clearly differentiate the type of headache. Patients

who had taken analgesics or anti-migraine medication prior to

ED admission were included only if there was no response to

drug and if more than 6 h had passed between use of the drug and

ED admission. Regular prophylactic migraine medications, other

than antidepressants and antipsychotics (as they may interact

with central nervous system effects of tramadol), were allowed.

Patients were allowed to participate in the study only once.After a detailed headache history, a general physical and

neurological examination was performed in all eligible patients

by the attending emergency physician. Diagnosis and eligibility

for the study were then confirmed by a neurologist. Baseline

headache characteristics and presence or absence of associated

symptoms (nausea, vomiting, photophobia and phonophobia)

were recorded. Severity of the headache was rated on a fourpoint verbal scale (0=none, 1=mild, 2=moderate, 3=severe) [19].After the collection of baseline data, patients were randomised to receive either tramadol 100 mg IM or diclofenac

sodium 75 mg IM. Randomisation was achieved by computerbased generation of random numbers. To assure blindness, tramadol preparation, which was 2 ml, was completed to 3 ml with

normal saline solution to look identical to diclofenac sodium 75

mg 3 ml preparation. Injections were prepared and applied by a

nurse who was not a part of the study. Neither the patient nor the

physician was allowed to learn the contents of the injection until

the end of the study period.After the injection, patients rated the severity of pain on the

four-point verbal scale at 30, 60, 90 and 120 min. At the end of

the study period (2 h), the presence or absence of associated

symptoms was recorded. Patients were questioned about whether

or not they would prefer the same injection for future admissions.

Any adverse events that could be related or not related to the drug

were also recorded. Patients and doctors globally evaluated the

drug on a 5-point verbal scale (0=very poor, 1=poor, 2=no opinion, 3=good, 4=very good). After these data were obtained the

doctor and the patient were informed of the content of the injection. Then, the patients with a pain score of 2 (moderate) or 3

(severe) or with unbearable associated symptoms received rescue

treatment at the discretion of the emergency physician. Patients

were followed up by telephone 48 h after the ED admission and

questioned about any headache recurrence, use of additional analgesics and any search for medical assistance.The primary outcome measure of the study was 2-h pain

response and positive response was defined as pain score

dropping from 3 or 2 to 1 or 0 within 2 h after the injection.

Secondary outcome measures were 2-h pain-free response,

48-h pain response, 48-h pain-free response, response to associated symptoms, rescue treatment, recurrence and adverse event

rates. Two-hour pain-free response was defined as pain score

dropping from 3 or 2 to 0 within 2 h. Positive 48-h pain

response was defined as patients with a positive 2-h pain

response without rescue treatment and recurrence at 48-h follow-up. Positive 48-h pain-free response was defined as

patients with a positive 2-h pain-free response without rescue

treatment and recurrence at 48-h follow-up. Response to associated symptoms was accepted as positive if the symptom

improved or was completely relieved.All demographic, baseline, study and follow-up data were

recorded on a standard study form by a resident or attending145physician. Data was then entered into SPSS 10.0 statistical software package (SPSS Inc. Chicago, IL) after the follow-up data

were recorded.The SPSS 10.0 statistical software package (SPSS Inc.

Chicago, IL) was used for statistical analysis. Power analysis

was performed with the NCSS-PASS 2000 Statistical software

package (Number Cruncher Statistical Systems, Kaysville, UT).

For categorical variables chi-square and Fishers exact chisquare tests were used. A two-tailed alpha value 0.05 was

accepted as statistically significant. Data were presented

descriptively as meansstandard deviation when appropriate.

Odds ratios (OR) and 95% confidence intervals (95% CI) of

odds ratios of groups were calculated to evaluate the probability

of whether one drug was superior to another. The closer the odds

ratio value is to 1, the more likely it is that the analysed parameter is similar in both groups.ResultsForty-seven patients with acute migraine headache admitted to the ED of Uludag University School of Medicine

between October 2003 and May 2004 were randomised to

tramadol (n=23) and diclofenac (n=24) groups (Fig. 1). Of

these 47 patients, 7 were excluded from final analysis due

to protocol violations (2 in tramadol, 3 in diclofenac

groups) and patients decision to leave the study (1 in tramadol and 1 in diclofenac groups). Demographic features

and migraine characteristics of the 40 patients that completed the study are shown in Table 1.Pain response rates and pain-free response rates at 2

and 48 h were similar for both drugs. Pain response rates

at 2 and 48 h for each trial arm are shown in Figure 2. At59 patients were eligible

47 patients were randomizedTramadol (n=23) Diclofenac (n=24)20 patients completed

the study12 patients were excluded, due to:5 patients, tension type headache3 patients, analgesic misure1 patient, hemiplegic migraine3 patients, secondary headaches20 patients completed

the studyFig. 1 Randomisation of the patientsTable 1 Demographic features and migraine characteristics of the patientsTramadol DiclofenacMale, n (%) 6 (30) 3 (15)

Female, n (%) 14 (70) 17 (85)

Mean ageSD 37.913.3 37.011.06

Mean diagnosis duration, yearsSD 6.474.70 6.053.52

Mean number of attacks per monthSD 2.701.17 2.401.23

Patients on prophylactic treatment, n (%) 3/20 (15) 3/20 (15)

Patients taken analgesic before ED, n (%) 5/20 (25) 6/20 (30)

Nausea, n (%) 18/20 (90) 15/20 (75)

Vomiting, n (%) 7/20 (35) 7/20 (35)

Photophobia, n (%) 17/20 (85) 18/20 (90)

Phonophobia, n (%) 16/20 (80) 18/20 (90)146a bc dFig. 2a-d Pain response rates at 2

(a, b) and 48 h (c, d). *p>0.05,

OR=1.00, 95% CI=0.224.35).

p>0.05, OR=1.52, 95%

CI=0.435.29. p>0.05, OR=0.81,

95% CI=0.232.84. p>0.05,

OR=0.64, 95% CI=0.172.31Fig. 3 Change in pain response rates in relation to time. *p>0.05,

OR=0.26, 95% CI=0.041.48. p>0.05, OR=2.45, 95%

CI=0.649.39. p>0.05, OR=1.33, 95% CI=0.305.92. p>0.05,

OR=1.00, 95% CI=0.214.70Fig. 4 Response to associated symptoms. *p>0.05, OR=1.30, 95%

CI=0.227.54. p>0.05, OR=0.36, 95% CI=0.255.10. p>0.05,

OR=0.56, 95% CI=0.122.60. p>0.05, OR=0.81, 95%

CI=0.163.94. () Positive response; () negative response60 min, pain score of 9 patients in tramadol group

declined to 1 (mild) and 2 patients pain was relieved completely. On the other arm of the trial, at 60 min, 12 patients

pain severity decreased to mild pain and 3 patients were

pain-free. Although there was a tendency towards earlier

response to diclofenac, no statistically significant difference was detected between the two groups in terms of pain

response rates at 30, 60, 90 and 120 min. Changes in the

number of patients with (+) pain response during the study

period at 30-min intervals is shown in Figure 3.There was no statistically significant difference

between tramadol and diclofenac groups in terms of

response rates to nausea, vomiting, photophobia and

phonophobia (Fig. 4). Rescue treatment was necessary

for 8 patients, 4 (20%) in the tramadol and 4 (20%) in

the diclofenac groups. Adverse events were observed in

a total number of 3 patients. Orthostatic hypotension

was observed in one patient in the tramadol group during discharge who recovered spontaneously with a few

minutes rest in sitting position without need for IV flu-147ids. In the diclofenac group, one patient described epigastric discomfort and one patient complained of worsening of nausea. Both events responded quickly to

symptomatic treatment.At 48 h follow-up, recurrence was reported by 2 (10%)

patients in the tramadol and 3 (15%) patients in the

diclofenac groups. One patient in the diclofenac group

was re-admitted to the ED due to recurrence. Tramadol

was rated good by 11 and very good by 3 of the patients.

Diclofenac was rated good by 14 and very good by 2 of

the patients. There was no statistically significant difference between the groups in terms of global evaluation of

the drugs by patients. Fifteen (75%) patients in the tramadol and 16 (80%) patients in the diclofenac groups stated that they may prefer the same injection for the future

admissions.DiscussionAcute migraine headache is a common presenting complaint to the ED and there is no defined standard abortive

treatment for acute attacks. Many specific (ergots and

triptans) and non-specific treatment options are used with

varying degrees of success. Opioids are one of the most

commonly chosen agents for the ED treatment of

headaches in the USA [10]. In this prospective, randomised, double-blind trial, efficacy of tramadol in

abortive treatment of acute migraine attack was evaluated

and compared with that of diclofenac sodium.Many studies used different outcome measures defining pain relief for migraine headache. Generally, pain

response rates for different drugs studied have ranged

between 45% and 88% [2, 3, 59]. In our study, 2-h pain

response rate for both tramadol and diclofenac was found

to be 80% and 2-h pain-free response rates were 35% and

45% respectively. Sustained pain response at 48 h was

found to be 65% for tramadol and 60% for diclofenac.

These rates are comparable to many of the drugs studied

for the treatment of acute migraine headache and are also

clinically acceptable.Associated symptoms generally subside with cessation

of headache pain. In our study, both drugs performed well

in relieving associated symptoms in parallel with pain.

Rescue treatment rates for different agents have been

reported to be between 11% and 33% [2, 4, 7, 8]. Rescue

treatment was necessary for a total number of 8 patients (4

in the tramadol, 4 in the diclofenac groups) in our study.

Headache recurrence rates of different treatments have

been found to be between 8% and 50% [3, 4, 8, 9]. 2/20

patients in the tramadol and 3/20 patients in the diclofenac

groups reported headache recurrence at 48-h follow-up.Need for rescue treatment and recurrence rates of both

drugs evaluated in our study were comparable to those of

other treatment options previously studied.Side effects were observed in 1/20 patients in the tramadol and 2/20 patients in the diclofenac groups. None

of the observed side effects were severe. Both drugs are

well tolerated by patients as 15 patients in the tramadol

and 16 patients in the diclofenac group stated that they

would prefer the same drug for future admissions. As

tramadol is a weak opioid, it is expected that it may

cause nausea and vomiting. Nausea or vomiting rates

after tramadol therapy have been reported between 0 and16.5% [1216]. In our study, we did not observe any

nausea or vomiting due to tramadol therapy. However, as

our study is small, our results may not reflect the real

side effect profile.One of the limitations of the study is that time to partial and/or complete relief was not recorded as a continuous variable. This limits the value of information about

response time and consequently the length of stay at ED.

However, more than half of the patients in each group

responded well enough to be discharged at 60 min. Other

limitations were due to the setting and design of the study;

the study was designed for the treatment of a single attack

with a single dose with IM route. Therefore, the study

does not provide information about usage in multiple

migraine attacks or prophylaxis and other routes of

administration and dosing regimens.As tramadol was not compared with placebo, because

it is not ethical to give placebo when effective treatment is

available, it is not possible to estimate how much of the

response was due to a placebo effect. The randomised

nature of our study minimises potential biases that may be

caused by the placebo effect.A common limitation of migraine studies originates

from selection of patients, as diagnosis of migraine is

based on clinical and historical information. Although IHS

criteria are widely used in migraine studies, it was reported that only 56% of patients with an ED discharge diagnosis of migraine met the IHS criteria [21]. The same

study reported that main deviations from the criteria were

observed in headache duration and number of prior

episodes. In our study we strictly controlled all the criteria and the diagnosis was confirmed by a neurologist.

Also, although the diagnostic criteria are not different

from the first edition, we chose to use the second edition

of the IHS criteria [20] as it addressed the common problems encountered in interpretation of the criteria.Although they are not the recommended first-line therapy, opiates are commonly used for the treatment of

benign headaches at ED [10]. Tramadol, because it is a

weak opioid, is placed in the second step of the analgesic

ladder of the World Health Organization [22]. Although148our results suggest that tramadol is an effective agent in

the treatment of acute migraine headaches, we do not

encourage its use as a first-line treatment. However, tramadol can be preferred in patients who are unresponsive

to first-line therapy or patients with contraindications for

NSAIDs or triptans. In conclusion, in selected patients,

tramadol 100 mg IM may be an effective and reliable

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