Abstract
Objectives
Tramadol is a synthetic centrally-acting opioid analgesic. The newly developed extended-release formulation of tramadol offers a more stable plasma concentration and could improve patients' compliance. The purpose of this study was to evaluate the efficacy, safety, and adverse events of extended release tramadol in Taiwanese patients with moderate to severe chronic noncancer pain.
Methods
Sixty-six patients with moderate to severe chronic noncancer pain previously treated with conventional tramadol but unsatisfied with its efficacy were enrolled from four medical centers. The patients received the extended-release tramadol once daily for a week.
Results
The usage of extended-release tramadol was more efficacious as the patients' visual analog scale score dropped significantly (−16 ± 14.1). In this study, the reported adverse events were similar to those of previous studies. Thirty patients reported adverse events and one patient reported a serious adverse event but was justified unrelated to the study drug. The most common adverse event was dizziness, followed by vomiting, nausea, somnolence, and constipation in sequence. In this study, patients with dizziness were observed to have a lower initial pain score (p = 0.032). Furthermore, the rate of premature termination and dizziness was closely correlated (p = 0.027).
Conclusion
Patients with chronic pain could obtain significantly better pain relief after the switch to larger doses of extended-release tramadol with safety and without severe adverse effects in a short period of time. Less severe adverse effects (no life-threatening event) was the leading cause of premature termination.
Keywords
dosage forms: extended-release preparations; pain measurement: visual analogue scaletramadol;
1. Introduction
Tramadol is a commonly used synthetic opioid analgesic mainly acting on the central nervous system. Two major pathways have been found for its action: agonistic binding to μ-opioid receptors and inhibiting the reuptake of norepinephrine and serotonin.1 The pharmacokinetic, efficacy, and safety properties of tramadol have made its use three to four times a day a success in patients with moderate to severe chronic pain. Extended-released tramadol, a newly developed, modified-release tablet, would be advantageous for day-long duration and less drug plasma variation compared with the conventional form of tramadol.2, 3 The purpose of this study was to evaluate the efficacy, safety, and adverse events associated with extended-release tramadol in Taiwanese patients with moderate to severe chronic noncancer pain.
2. Methods
This study was registered in the International Research-based Pharmaceutical Manufacturers' Association, Taiwan, R.O.C. on October 2, 2008 with study number CTRA000ATW01,(http://www.irpma.org.tw/chinese/cgi/07_pms.php). The comprehensive protocol and the informed consent form were approved by the Institutional Review Board of each participating center. Informed consent was obtained from each patient before the trial began. This clinical study was conducted pursuant to the latest revised version of the Declaration of Helsinki.
This study was a multicenter, open label, noncomparative, observational study. Sixty-six adult patients of both sexes with moderate to severe chronic noncancer pain (whose visual analog scale score [VAS] ≥40) from four centers were enrolled. These patients had pain mainly of the musculoskeletal system (such as low back pain or degenerative joint disease), neurologic system such as postherpetic neuralgia (PHN), diabetic neuralgia (DBN), trigeminal neuralgia, or complex regional pain syndrome (CRPS), or combination of these two systems (such as low back pain with sciatica). These patients had been treated previously with conventional tramadol with or without acetaminophen for more than 1 week, but without avail of outstanding efficacy in their respective center (daily dosage of tramadol not more than 100 mg). They might take nonsteroidal antiinflammatory drugs (NSAIDs), anticonvulsants, and/or antidepressants as adjuvants, and they would continue using these adjuvants throughout the study period. The patients were admitted for treatment consecutively during the time period from November 14, 2008 to January 6, 2009.
Demographics and other baseline characteristics including age, sex, weight, height, and pain score were recorded at Visit 1 (Day 1). The patients then received a prescription of extended-release tramadol 200 mg once daily for 1 week. At Visit 2 (Day 8), the patients were subject to evaluation of the efficacy, safety, and adverse events of the tested drug.
Efficacy was mainly measured by the difference of VAS between two visits. The safety endpoints included (1) the pain control status assessed by VAS, (2) the adverse events or other serious events that might confuse patients, and (3) vital signs (sitting blood pressure, pulse rate) assessment and physical examination during the study period.
The main exclusion criteria were as follows: (1) hypersensitivity to tramadol, any other component formulations, or opioid; (2) sustained acute intoxication with centrally acting analgesics, opioids, or psychotropic drugs; (3) currently use of monoamine oxidase (MAO) inhibitors or history of MAO inhibitor use within the past 14 days; (4) uncontrolled epilepsy; (5) pregnancy or lactation; (6) a severe medical condition that might hinder the study, e.g., severe renal (creatinine clearance <30 mL/min) or hepatic impairment; and (7) use of other investigational drugs at the time of enrollment.
For continuous monitoring of the pain score, the descriptive statistics of the patients' VAS were summarized as number, mean, standard deviation, median, minimum, and maximum for each visit. The changes of the VAS were statistically analyzed with paired Student t-test and p < 0.05 was considered statistically significant.
Descriptive statistics were used to analyze adverse events. The incidence of adverse events was calculated by the ratio of the patients who experienced specific adverse events among total patients. The patients' vital signs were also analyzed with descriptive statistics.
The initial VAS of the patients with adverse events was compared with those without adverse events throughout the study with the Student t-test. The patients who prematurely terminated treatment were compared with those who completed the study by chi-square test. The reasons for premature termination of treatment were also analyzed.
3. Results
The demographics of the 66 patients who participated in our study are shown in Table 1; 31 (47%) were males and 35 (53%) were females. Their mean age was 66.4 ± 11.0 years. Average height was 159.6 ± 11.3 cm and average weight was 77 ± 8.2 kg. With VAS ranging from 0 to 100 mm to assess the intensity of pain, the mean value of 64.7 ± 16.8 mm was obtained at Visit 1. These patients with chronic pain who came for advice and treatment were grouped into three categories: 30 (45.4%) for low back pain; 23 (34.8%) for neuropathic pain; and 13 (19.6%) for osteoarthritis. Before the study, all patients had been regularly treated with conventional tramadol with or without acetaminophen, of whom 33 (50%) took NSAIDs, nine (13.6%) took anticonvulsants, and three (4.5%) took amitriptyline for reinforced analgesic medication.
Fig. 1 shows the disposition of patients in this study. Fifty-one patients (77.3%) finished the entire study and 15 patients (22.7%) withdrew before the end of the study. The reasons for early discontinuance are listed in Fig. 1. To analyze the efficacy, we evaluated the patients' pain intensity with scoring of VAS. Pain scores were significantly decreased at Visit 2 (p < 0.001). At the end of the study, the mean value of decrease in pain intensity was −16.0 ± 14.1 mm. The VAS pain scores are listed in Table 2. Of the three different subdivided groups of our patients with chronic pain, their pain scores decreased in sequence of ranking: the score of the osteoarthritis group decreased from 6.9 to 5.8, the low back pain group from 6.67 to 5.33, and the neuropathic pain group from 6.64 to 4.14. These findings are listed in Table 3.
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During the treatment period, patients who experienced adverse events were recorded with detailed intensity, outcome, and causality (Table 4). Thirty patients (45.4%) reported 49 adverse events, of which 46 (93.8%) might be related to the tramadol usage. Among the 49 adverse events, 29 (59.18%) were mild in intensity and 20 (40.82%) were moderate in intensity. Forty-six adverse events (93.88%) were resolved and three (6.12%) were incompletely resolved with some residual effects. Ten patients (15.1%) discontinued the treatment because of adverse events. Dizziness remained the most common adverse event that caused premature termination of treatment.
Commonly occurring adverse events (≥5%) include 20 instances of dizziness (30.3%), eight of vomiting (12.1%), five of nausea (7%), four of somnolence (6%), and four of constipation (6%). These adverse events are presented in Table 5. One severe extraordinary adverse event reported during the study involved admission to the hospital of a 53-year-old man due to abdominal pain. During hospitalization, computed tomography of the abdomen was performed with no specific findings. Abdominal echo study showed only moderate fatty liver. He was treated with antibiotics and was soon discharged and advised to be followed up at the outpatient clinic. This adverse event was justified unrelated to the study drug.
Further analysis revealed that patients who experienced dizziness had lower initial pain scores (58 ± 16.4) in comparison with those patients without dizziness (67.6 ± 16.4); these scores had statistical significance (p = 0.032, Fig. 2). Furthermore, the rate of premature termination of treatment in patients with dizziness (8 of 20) was higher than in those patients without dizziness (7 of 46), which was statistically significant (p = 0.027).
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The patients' vital signs were assessed in two visits. No clinically significant changes in diastolic pressure and heart rate were observed. The average systolic pressure decreased significantly (p = 0.007) after 1-week extended-release tramadol treatment. The changes of vital signs are summarized in Table 6.
4. Discussion
Chronic pain frustrates many patients and physicians and has become a major health problem that demands a comprehensive approach with the integration of pharmacologic and nonpharmacologic treatments. Usually, we initiate pain management with NSAIDs. However, long-term use of NSAIDs may deteriorate renal function and cause gastrointestinal problems, and the use of certain drugs such as aspirin is contraindicated because some patients are allergic. Long-term use of opioids for chronic pain is still not fully acceptable because of the possibility of addiction and sanction of regulations. Tramadol may be considered a preferable choice for those patients with moderate to severe chronic noncancer pain because of its low addiction rate and favorable safety profile.4, 5, 6 A prescribed analgesic may serve as an additional therapy for inadequate pain control.7, 8 Compared with immediate-release tramadol capsule, extended-release tramadol offers an advantageous pharmacokinetic profile such as sustained plasma drug concentration for at least 24 hours.9 Although the pain scores obtained from once-daily extended-release tramadol do not differ from those of immediate-release tramadol,10 the extended-release tramadol might offer extra benefit by improving patients' compliance.
In our study we have witnessed the unique power of extended-release tramadol in pain relief within a short period of time, yet another value it provides is significant decrease of VAS. Our results, which revealed its highly reliable safety profile including minimal changes in vital signs, better systolic blood pressure control, and less severe adverse events, are compatible with other studies. A significant decrease in systolic blood pressure might be associated with decreased pain after the use of extended-release tramadol. Diastolic blood pressure and heart rate also decreased at simultaneously, but did not reach a harmful level.
Adverse events associated with extended-release tramadol include dizziness, drowsiness, nausea, vomiting, and constipation, all of which could be noted in the use of all formulations.4, 5, 10, 11 Our adverse events ratio was similar to the other recent clinical studies of extended-release tramadol. Adverse events have become the leading cause of premature termination of treatment compared with other factors (e.g., lack of efficacy). Two-thirds of the premature terminations were due to adverse events.
Our patients had previously been treated with conventional tramadol with or without acetaminophen for more than 1 week, but they did not see efficacy (daily dosage not more than 100 mg). After they were enrolled in the study, the patients were given a larger dosage of extended-release tramadol (200 mg). Is this titration process too short? Petrone et al12 revealed that longer titration time was positively relative to lower adverse event-related early withdrawal rates and better gastrointestinal tolerability for the tramadol immediate-release formulation. However, slow titration may cause the lack of efficacy, which may in turn be the cause of premature termination.
Dizziness was the major adverse event responsible for premature termination of treatment in our study. It contributed to 60% of early discontinuation of treatment; this finding suggests that when we prescribed extended-release tramadol in our clinic, dizziness might be the key factor responsible for poor compliance.
In our study, patients with dizziness had a lower initial VAS compared with those patients without dizziness, a finding that has not yet been pointed out in other studies. Does it imply that patients with less pain will be more easily subjected to dizziness with the use of extended-release tramadol? Patients' pain scores should be considered when extended-release tramadol is prescribed to avoid dizziness.
Interestingly, our patients who experienced vomiting and who experienced nausea are not overlapping. Only one patient had both symptoms of nausea and vomiting. The rate of vomiting (12.1%) was higher than the rate of nausea (7%). In a previous study, differences were seen in the ratios of certain adverse gastrointestinal and central nervous system events between extended-release and immediate-release tramadol.13
The limitations of our study include lack of choices of dosage regimens, lack of control group for comparison, and a short study period. Beaulieu et al14 reported that dizziness rates were lower (60.0% to 11.8%) as the daily dosage of controlled-release tramadol was shifted from lower ones (200–250 mg/day) to the higher one (400 mg/day). In our study, we had to use only one form of preparation of extended- release tramadol (200 mg/day), which was against dosing flexibility. The reason why we were sure that a 1-week observation period could tell us something was because tramadol's effects and side effects usually occurred during the first week.4 Whether the adverse events come from the study drug or other clinical condition needs further analysis.
We did not have a washout of concurrent pain medication for our patients, and it's hard to be performed under nowadays ethical consideration. NSAIDs and anticonvulsants might not interfere with the effects of extended-release tramadol. Amitriptyline does share similar serotonin norepinephrine reuptake inhibition pathways with tramadol,15, 16 but the number of affected patients was small (three) and the dosage was low (25 mg). Concurrent use of tramadol with low-dose amitriptyline might not have synergistic or antagonistic effects. Therefore, our patients kept the same dosage as before throughout the study period.
Finally, in our study discontinuation of the treatment was a shortcoming, which made it more difficult to find out the factors that affect adverse events. Maybe these patients who withdrew from the study early were the people who require more attention.
Acknowledgments
This study was sponsored by Novartis Co., Ltd. in Taiwan. We would like to thank our clinical staff for their important contributions to the study at all study sites.