Efficacy of tramadol vs meperidine in vasoocclusive sickle cell crisis
Original Contribution
Efficacy of tramadol vs meperidine in vasoocclusive sickle cell crisis
Belkan Uzun MDa, Zeynep Kekec MDb,?, Emel Gurkan MDc
aEmergeny Department, Tekirdag Government Hospital Tekirdag, Turkey
bDepartment of Emergency Medicine, Cukurova University Medical School, Adana-Turkey
cDepartment of Hematology, Cukurova University Medical School, Adana-Turkey
Received 8 October 2008; revised 12 January 2009; accepted 12 January 2009
Abstract Despite progress in management, patients with Sickle cell disease who are experiencing acute painful episode are often incompletely treated. We compared meperidine and tramadol with respect to their effects on the hemodynamics and pain relief in patients with sickle cell disease who were admitted to the emergency department with painful crisis. A total of 68 patients with sickle cell disease were randomly assigned to receive either tramadol 1.5 mg/kg (n = 34) or meperidine 1 mg/kg (n = 34). Hemodynamic parameters were recorded at regular intervals after analgesic infusions. Pain intensity and relief were documented by visual analog and pain relief scale, respectively. Sedation level was defined according to Ramsay sedation scale. Both meperidine and tramadol administration resulted in a significant reduction in systolic and diastolic blood pressure after 2 hours (P b .05). Efficacy in pain relief between the analgesics was more rapid and better in the meperidine group, although the degree of relief were significantly improved compared to baseline levels in both groups (P b .05). Sedation was more commonly seen in the meperidine arm. None of the patients had experienced neurotoxicity. In summary, both agents had proven safe and effective for emergent use in patients with sickle cell disease. Avoiding meperidine injections as recommended with previous guidelines needs to be carefully reconsidered especially when low doses are mentioned.
(C) 2010
Introduction
The vasoocclusive crisis is a common reason for emergency department (ED) visits and hospitalizations in patients with Sickle cell disease . Bone infarction due to vasoocclusion of the bone marrow vasculature, causing release of Inflammatory mediators that activate afferent nociceptors, is suggested to be the main mechanism for painful episodes [1]. The severe pain is believed to be caused
* Corresponding author. Tel.: +90 093222352681, +90 532 7156894
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E-mail address: [email protected] (Z. Kekec).
by increased intramedullary pressure secondary to an acute inflammatory response to vascular necrosis of the bone marrow by sickled erythrocytes [2]. The approach to the patient with SCD presenting with pain consists of aggressive pain relief using opiates and other analgesics. There are a number of analgesic agents that can be used in such patients. Many studies have reported oligoanalgesia in ED patients who are having pain, including patients with SCD [3]. Most of the guidelines recommend narcotics, particularly mor- phine, along with fluid hydration as the Standard supportive care for treating painful episodes [4,5]. However, despite concerns about neurotoxicity, meperidine is still among the most commonly used opioids in many centers. On the other
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hand, several studies suggested that tramadol, which is a weak opioid agonist, is useful in pain control with efficacy equivalent to meperidine [6-9]. The aim of this study was to determine the effectiveness of meperidine vs tramadol in the management of painful crisis in adult SCD patients.
Patients and methods
Patients with SCD who presented to the ED of our tertiary referral hospital with acute painful episode over an 18-month period were included in this study. There were 149 sickle patient visits to the ED for various reasons, of which 68 patients were eligible. Exclusion criteria were as follows: patients less than 16 years of age; known allergies to the study drugs; pregnancy; antidepressant/monoamine oxidase inhibitor therapy; serious cardiac, pulmonary, or neurologic disorder; renal failure. The subjects consisted of 68 patients with SCD who presented with acute painful crisis. The mean age of patients were 24.9 +- 6.1 years (mean +- SD). The workup of the patients with vasoocclusive crisis included a complete history, a physical examination, selected laboratory tests, and a search for precipitating factors. The Visual analog scale consisting of a horizontal line labeled from 0 to 10, with 0 indicating “no pain” and 10 indicating “worst pain possible,” was used for evaluating pain intensity, and those patients with a VAS score of 5 and greater were included [2]. Exclusion criteria were as follows: known allergies to any of the agents used (meperidine, tramadol), those patients on antidepressant or monoamine oxidase inhibitor treatment, pregnancy, and patients younger than 16. For each patient, the duration of the pain before presentation, the site(s) of the pain, and the medications used before presentation to the hospital were recorded. After insertion of intravenous line and hydration, patients were randomly assigned to receive either meperidine or tramadol. The initial doses were 1 and
1.5 mg/kg, both intravenous slow infusion in 20 minutes, respectively. After initial doses of both agents, vital signs, oxygen saturation with pulse oximetry, VAS score, and the degree of pain relief and sedation level defined according to Ramsay sedation scale were recorded [10]. Relief was defined as a score of 2 or greater on a pain relief scale (0 = no relief, 1 = little relief, 2 = moderate relief, 3 = good relief, 4 = complete relief) or a 50% reduction from the upper end of the pain intensity scale. [2]. Sedation level was 1 = awake and alert; 2 = occasionally drowsy, easy to arouse; 3 = frequently drowsy, arousable, drifts off to sleep during conversation; 4 = somnolent, minimal, or no response to stimuli [10]. Measurement of hemodynamic parameters were performed at baseline, 15, 30, 60, 90, and 120 minutes after the injections. Additional analgesic medication was prescribed if VAS score was 5 or higher after 2 hours of narcotic administration. Patients whose opioid requirement was more than 2 times in the 4-hour period or who have the signs and/ or symptoms of infectious disease requiring parenteral
Table 1 Characteristics of study population
antibiotic treatment were hospitalized, whereas those patients with mild pain not requiring parenteral medication with a VAS score less than 3 were allowed home. The study was approved by the local ethics committee, and all patients provided written informed consent to participate in the study. The statistical software package SPSS 11.5 (SPSS, Inc., Chicago, IL) was used, and P <= .05 was considered significant. The Mann-Whitney U and Kruskal-Wallis tests were used to compare means.
Results
The study population consisted of 68 patients with SCD with acute painful episodes. Characteristics of the patients with SCD within the meperidine and tramadol groups are given in Table 1. There were 34 patients treated with meperidine and 34 patients treated with tramadol. There was no statistically significant difference between groups when demographic features including age, sex, vital signs, pain intensity, accompanying infections, and laboratory findings were compared. Of the 68 patients, 11 (16.1%) had accompanying fever with no significant difference between groups. After admission, patients were assigned randomly to receive either meperidine or tramadol. Sedation was the most common adverse effect in the meperidine-receiving patients, whereas those within the tramadol group complained mostly of nausea, vomiting, and headache. Additional analgesics were indicated in 38% of the patients within the meperidine group, whereas 73% of the patients within the tramadol group required medication within 2 hours. This difference was statistically significant (P b .05) (Table 1).
Table 2 summarizes the changes in vital signs observed in meperidine and tramadol group. There was a 25 +- 3 mm Hg decrease in systolic blood pressure (SBP) at 2 hours in
|
Parameter mean (SD) or count (%)
|
Meperidine (n = 34) |
Tramadol (n = 34) |
P |
|
Mean age |
24.9 (6.5) |
24.8 (5.8) |
NS |
|
Male sex |
26 (76) |
23 (68) |
NS |
|
S-thalassemia |
1 (3) |
0 (0) |
NS |
|
Hemoglobin (g/dl) |
9.0 (1.4) |
8.8 (1.3) |
NS |
|
White cell count (x109/L) |
16.7 (5.6) |
16.0 (4.5) |
NS |
|
Pulse oximetry (level) |
99.1 (1.3) |
99.0 (2.0) |
NS |
|
Initial VAS score |
7.5 (1.1) |
7.5 (1) |
NS |
|
Prior analgesic use |
29 (85) |
29 (85) |
NS |
|
Duration of pain a (h) |
19.9 (16) |
22.2 (16.6) |
NS |
|
Additional analgesic b |
13 (38) |
25 (73) |
.03 |
|
Hospitalization |
11 (32) |
15 (44) |
NS |
|
NS indicates nonsignificant. a Before admission. b After admission. |
|||
patients receiving meperidine (P b .05), whereas within the tramadol group, there was 8 +- 5 mm Hg decrease (P b .05). This reduction was more significant in the meperidine group as compared with the tramadol-receiving patients at 30 minutes and afterward (P b .05).
Meperidine
25 +- 10
23 +- 3
22 +- 3
21 +- 2
21 +- 2
21 +- 2
21 +- 3 ?
PR indicates pulse rate; OS, % oxygen saturation; RR, respiratory rate.
* P b .05, difference from baseline values.
Similarly, a statistically significant decrease in diastolic blood pressure at 2 hours was observed in both groups, which was more pronounced within the meperidine group. The difference between both groups was seen at 15 minutes and afterward (P b .05).
In both group of patients, there was a trend to a slower pulse rate compared to baseline levels. The decrease in pulse rate was 7 +- 3 and 5 +- 4 beats/min after 2 hours of administration in meperidine and tramadol groups, respec- tively (P b .05). The mean pulse oximetry readings were not significantly different from the baseline levels both within and between the groups (P N .05).
Despite that administration of both opioids had resulted in a decrease in pain intensity in both groups as measured by a 1-to-10 VAS, meperidine was more effective compared to tramadol. The difference in VAS scores was significant at 15 minutes and afterward between the 2 groups (P b .05). However, meperidine caused more sedation within the same period (Table 3). Efficacy in pain relief was more rapid and better in the meperidine group, although the degree of relief was significantly improved compared to baseline levels in both groups (P b .05). Notably, despite a significant decrease in pain intensity compared to baseline levels in the tramadol
Table 3 Evaluation of responses to therapy
Time Meperidine
Tramadol
arm, additional analgesic requirement was significantly higher (P b .05).
At the end of the study, 26 (38%) of the 68 patients were hospitalized. Among these, 11 and 15 were in the meperidine and tramadol arms, respectively. Despite that hospitalization rate was lower in the meperidine group, the difference was not statistically significant (P N .05).
Discussion
Acute sickle cell painful crisis is a common reason for ED admissions. Because of concerns about addiction and limited knowledge regarding the pharmacology and efficacy of opioid analgesics, patients with SCD presenting with painful episodes are often undertreated in EDs [3]. Despite well- designed guidelines for the management of such cases, there is still great variability between centers [11,12]. Physicians mostly use opioids that they are more familiar with rather than applying a standard protocol as suggested by the available scientific literature [13]. There are a number of opioid analgesics that can be used in sickle cell painful crisis. Among these, meperidine is the most commonly adminis- tered opioid analgesic used in EDs to treat patients with SCD experiencing painful episodes [12,13]. However, meperidine is not recommended for the treatment of painful episodes of SCD. The American Pain Society and the National Institutes
|
VAS |
Pain relief |
Sedation |
VAS |
Pain relief |
Sedation |
||
|
0 |
7.5 (1.1) |
0 (0) |
0.9 (0.1) |
7.6 (1.0) |
0 (0) |
1.0 (0) |
|
|
30 |
8.5 (1.7) |
0.7 (0.8) |
1.2 (0.4) |
7.5 (1.6) |
0.2 (0.4) |
1 (1.1) |
|
|
60 |
4.4 (2.4) |
1.5 (0.8) |
1.4 (0.6) |
6.7 (2.3) |
0.5 (0.8) |
1.0 (0.2) |
|
|
120 |
3.5 (2.9) ? |
1.9 (1.1) ? |
1.4 (0.6) ? |
6.4 (3.0) ? |
0.7 (1.1) ? |
1.2 (0.5) |
|
|
* P b .05 according to baseline. |
|||||||
of Health have recommended that meperidine not be considered as first-line drug in the treatment of patients with SCD because it is less effective and has a higher incidence of side effects compared to morphine, which is proposed as the analgesic of choice [14]. However, despite concerns about normeperidine, meperidine is still the most commonly used narcotic for patients in pain at our and many other institutions. We chose to look at its safety and efficacy particularly when it came to adverse effects of hypotension or unusual drowsiness.
Tramadol HCl has also been a frequently used analgesic for the treating patients with painful crises in recent years. However, published data about the usage of tramadol for sickle cell painful crisis in adults are limited [6,7]. Tramadol is a centrally acting analgesic binding to the mu-opioid receptor, inhibits norepinephrine and serotonin reuptake, and induces minimal respiratory depression [15]. Compared with meperidine and morphine, minimal respira- tory effect associated with tramadol has made this agent preferable. Tramadol was suggested for use in moderate to severe pain due to vasoocclusive crisis in the pediatric patients [6]. In this controlled study, we compared the efficacy and safety of meperidine vs tramadol in the management of acute sickle cell painful crisis. We used equivalent Analgesic doses of these agents as reported in the literature, tramadol having 75% of the meperidine potency [16]. Despite that there was a marked decrease in pain intensity with both agents, meperidine was more efficient and caused a more rapid response. There was a statistically significant difference in pain relief when both agents were compared according to VAS and pain relief score. However, additional analgesic requirement in tramadol-treated patients was significantly higher. Taking these data into consideration, we agree with the previous proposals that tramadol might be considered for the management of moderate- to severe-intensity painful episodes in combina- tion with other nonopioid analgesics [6,17].
We found a slight decrease in respiratory rate with meperidine but no hypoxia as measured by pulse oxygen saturation. It is likely that relief of pain resulted in resolution of anxiety in these patients. There were no significant changes with tramadol in respiratory parameters. In a study performed by Mildh et al [16] comparing effects of meperidine and tramadol on respiratory and hemodynamic parameters in healthy volunteers, authors similarly did not observe any Clinically significant changes in pulse oxygen saturation with only a slight decrease in meperidine arm . In our study, after infusion of both agents, a significant decrease in SBP and DBP occurred, which was more prominent in the meperidine arm. In general, present literature indicate that hemodynamics of patients do not change after tramadol injections because tramadol binds weakly to Opioid receptors in central nervous system [18]. Various studies mostly consisting of surgical patients demonstrated no significant change in arterial tension [16,19,20]. However, there is no prospective controlled trial in the literature comparing the
effects of meperidine and tramadol in patients with SCD. Our results suggest that meperidine should be cautiously used in patients with SCD especially when the acute vasoocclusive crisis is due to dehydration. However, this observation still needs to be confirmed by Prospective trials. Seizures due to meperidine use in patients with SCD were reported in 1% to 12% of the cases [12]. In a retrospective study, the incidence of seizures associated with meperidine is also found to be very small as 0.4% [21]. None of our cases experienced any signs of neurotoxicity in our study. However, it should be emphasized that concerns about neurotoxicity mostly related with meperidine use in higher doses [14]. To summarize, although tramadol provided some degree of pain relief, it was not nearly as effective as meperidine. Twice as many patients receiving tramadol required additional analgesia as in the meperidine group. The degree of pain relief on the VAS score for tramadol only decreased by 12 mm, although statistically significant one could argue whether this is clinically significant. Although it was not associated with any significant sedation or changes in hemodynamics, it was not nearly as effective as meperidine. There was no evidence that the degree of sedation or hypotension was clinically significant in any of these patients.
In our institution, we apply standard treatment policies including fluid hydration along with narcotics. The results of our study demonstrated that either meperidine or tramadol is useful for initial ED treatment in patients with severe acute sickle cell pain crisis. Avoiding meperidine injections as recommended with previous guidelines needs to be carefully considered especially when low doses are mentioned. Rather than totally abandoning meperidine use, a combined approach involving a shift from meperidine to morphine derivatives may be considered as an option in patients with a severe and a long-lasting crisis. More controlled trials are needed to compare the safety and efficacy of these agents in management of acute sickle cell painful crisis.
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