acetaminophen combination capsules for the management of chronic pain: a comparative trial

CLINICAL THERAPEUTICS®/VOL.23, NO. 9, 2001

Tramadol/Acetaminophen Combination Tablets and Codeine/Acetaminophen Combination Capsules for the Management of Chronic Pain: A Comparative Trial William S. Mullican, MD, 1 and Joseph R. Lacy, MD, 2 for the TRAMAP-ANAG.O06 Study Group* /Indiana UniversitySchool of Medicine, Evansville Centerfor Medical Education, Evansville, Indiana, and 2Departmentof Neurology, PaloAlto Medical Foundation, Palo Alto, California

ABSTRACT

Background: Opioid/acetaminophen (APAP) combination analgesics are widely prescribed for the relief of moderate pain. Tramadol is a synthetic analgesic that has been shown to be effective both alone and in combination with APAP. Objective: The purpose of this study was to compare the efficacy and tolerability of tramadol/APAP tablets with codeine/APAP capsules. Methods: This 4-week, randomized, double-blind, parallel-group, active-control, doubledummy, multicenter trial compared tramadol/APAP (37.5 mg/325 mg) with codeine/APAP (30 mg/300 mg) for the management of chronic nonmalignant low back pain, osteoarthritis (OA) pain, or both in adults. Pain relief (scale, 0 = none to 4 = complete) and pain intensity (scale, 0 = none to 3 = severe) were measured 30 minutes and then hourly for 6 hours after the first daily dose each week. Patients and investigators assessed the efficacy (scale, 1 = poor to 5 = excellent) of each medication, and patients recorded daily doses of study and rescue medications. Results: A total of 462 patients (mean age, 57.6 years) were randomly assigned to treatment, with 112 (24%) reporting chronic low back pain, 162 (35%) reporting OA pain, and 188 (41%) reporting both low back and OA pain; 309 patients (67%) received tramadol/ APAP and 153 (33%) received codeine/APAP. Pain relief and changes in pain intensity were comparable from day 1, as early as 30 minutes after the first dose, and lasted for at least 6 hours. Total pain relief scores (11.9 for tramadol/APAP; 11.4 for codeine/APAP) and sum of pain intensity differences (3.8 for tramadol/APAP; 3.3 for codeine/APAP) were also comparable throughout. Overall assessments of efficacy by patients (mean score 2.9 in each treatment group) and investigators (mean score 3.0 for tramadol/APAP, This paper was presented in part at the Annual European Congress on Rheumatology--EULAR 2000, June 22, 2000, Nice, France. *Members of the TRAMAP-ANAG-006 Study Group are listed in the Acknowledgments.

Accepted for publication August 8, 2001. Printed in the USA. Reproduction in whole or part is not permitted.

0149-2918/01/$19.00

1429

CLINICAL THERAPEUTICS ~

2.9 for codeine/APAP) were similar for the 2 treatment groups. Equivalent mean doses (3.5 tablets or capsules daily) and maximum daily doses (5.5 tablets or 5.7 capsules) were used in the 2 treatment groups. The overall incidence of adverse events was comparable, with a significantly higher proportion of patients in the codeine/APAP group reporting somnolence (24% [37/153] vs 17% [54/309], P = 0.05) or constipation (21% [32/153] vs 11% [35/309], P < 0.01) and a larger proportion of patients in the tramadol/ APAP group reporting headache (11% [34/309] vs 7% [11/153], P = 0.08). Conclusion: The results of this study suggest that tramadol/APAP tablets (37.5 mg/325 mg) are as effective as codeine/ APAP capsules (30 mg/300 mg) in the treatment of chronic nonmalignant low back pain and OA pain and are better tolerated. Key words: tramadol, acetaminophen, tramadol/acetaminophen, codeine/acetaminophen, osteoarthritis, back pain. (Clin Ther. 2001;23:1429-1445) INTRODUCTION In a recent US poll, 89% of adults aged >18 years reported experiencing pain at least monthly, l However, 64% of pain sufferers said they consult a physician only when they can no longer tolerate the pain, and only 42% who do see a physician believe that the physician completely understands how the pain makes them feel.l The 1-year prevalence of low back pain is -15% to 20% in the United States, but the lifetime prevalence may be as high as 70%. 2,3 It is the most common cause of disability in patients aged <45 years. 4 Similarly, >70% of patients aged >65 years have radiographic evidence of osteoarthritis (OA) in at least 1 joint, and pain is the 1430

most common presenting symptom. 5 0 A is the most common cause of disability in all adults aged >18 years. 6 Because there is no cure for OA, the main goals of therapy are to control pain and symptoms (eg, stiffness or limited range of motion), minimize disability, and educate patients and caregivers about the disease. 7 Acetaminophen (APAP) is used as a first-line agent for low back pain8 and is recommended by the American College of Rheumatology as first-line therapy for OA. 7 APAP is a rapid-acting, safe, and effective agent for mild to moderate pain in doses _<4 g/d. 9 However, when APAP fails to control chronic OA or back pain, patients and physicians historically have been faced with choosing nonsteroidal anti-inflammatory drugs (NSAIDs) or opioids, i°'lj Despite popular perception, inflammation is thought to play only a minor role in the pathogenesis of OA pain. 12 Therefore, although NSAIDs are effective analgesics, their anti-inflammatory properties may contribute little to OA pain relief. 13 Furthermore, NSAIDs have been associated with renal 14,15 and gastrointestinal (GI) 16toxicity during chronic use. Although the newer cyclooxygenase (COX)-2-specific NSAIDs may be associated with a lower incidence of GI ulcers, GI bleeding has also been reported with these agents. 17 Nephrotoxicity 18 and cardiotoxicity t9 have been reported, and the renal effects and overall safety profile of COX-2 inhibitors remain to be determined with long-term clinical use. 2° Long-term opioid therapy also presents potential problems. Patients and clinicians are often concerned about the potential for addiction, which may limit prescribing and use, leading to inadequate management of pain. 21 Furthermore, tolerance to the analgesic effect of opioids develops

W.S. MULLICAN AND J.R. LACY

with continued u s e . 22 The overall adverseevent profile commonly seen with opioid therapy, including constipation and somnolence, may be particularly limiting in elderly patients. 23 Tramadol is an effective and safe analgesic for moderate to moderately severe chronic pain and an alternative treatment to NSAIDsY -27 It can control pain due to a variety of chronic disorders, including OA,27 29 low back pain, 3° fibromyalgia, 31'32 and diabetic neuropathy. 33 Tramadol is a centrally acting synthetic analgesic agent. Although its mode of action is not completely understood, animal tests indicate that at least 2 complementary mechanisms appear applicable: binding of the parent compound and the M1 metabolite to ~-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. 34 Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone. 35 Because of this mechanism of action, the adverseevent profile of tramadol differs from that of NSAIDs or traditional opioids. 36 An independent panel of drug-abuse experts concluded that tramadol is unlikely to be abused (0.5-1.0 case per 100,000 patients) 37 and is not a scheduled drug. However, tramadol is not recommended for patients with a tendency for opioid abuse or dependence. 38 Two separate studies have shown that in selected patients, starting with lower doses of tramadol (25-50 mg/d) and titrating the dose slowly over 10 to 16 days (increasing the total daily dose by 25 to 50 mg every 3 days) may reduce drug discontinuation due to adverse events such as nausea, vomiting, and dizziness. 39,4° Seizures have been reported in patients taking tramadol, and the risk may be increased by concomitant use of selective

serotonin reuptake inhibitors, tricyclic antidepressants, opioids, monoamine oxidase inhibitors, neuroleptics, or other drugs that increase the seizure threshold. 38 Combination analgesics are widely used to manage moderate pain38; 5 of the top 200 prescription medications sold in the United States in 2000 (including generics) were opioid/APAP combination products. 41 Tramadol and APAP have demonstrated synergy in certain combinations in mice. 42 The combination of tramadol with APAP has been found to be more effective than tramadol or APAP alone in clinical studies of acute pain from dental surgery. 43 This 4-week, randomized, double-blind, parallel-group, active-control, doubledummy, multicenter study compared the tolerability and efficacy of multiple doses of a combination tablet of tramadol/APAP (37.5 mg/325 mg) with codeine/APAP (30 mg/300 rag) capsules in adult patients with chronic nonmalignant low back pain, OA pain, or both. PATIENTS AND M E T H O D S

Study Population A total of 462 patients with chronic nonmalignant low back pain, OA pain, or both were enrolled. The study was conducted at 58 US centers and followed a common protocol approved by the investigational review board and ethics committee at each site. During screening and before the initiation of any study-related procedures, all patients gave informed written consent. Patients were eligible for the study if they had mild to moderate nonmalignant chronic pain (persistent pain for ->6 months) as a result of low back pain or 1431

CLINICAL THERAPEUTICS*

OA of any joint. Patients were required to be >18 years of age and in good health. Women were included only if they were not pregnant, were using appropriate birth control methods, had been surgically rendered sterile, or were postmenopausal. Exclusion criteria included a history of seizures; alcohol or drug abuse within the past year; suicidal tendencies; use of monoamine oxidase inhibitors, tricyclic antidepressants, neuroleptics, or other drugs that may have reduced the seizure threshold; or any known allergy, sensitivity, or contraindication to a study medication.

Study Design Patients discontinued all other analgesics for at least 6 hours before study entry and were randomized in a 2:1 fashion to receive tramadol/APAP tablets or codeine/APAP capsules for 4 weeks. Randomization was based on permuted blocks; the randomization schedule was prepared before the trial. Simultaneous use of placebo capsules in the tramadol/ APAP group and placebo tablets in the codeine/APAP group (the "doubledummy" technique) maintained the double blind. Placebo tablets and capsules were matched in appearance to the corresponding study medications. Study drugs were packaged in identical containers. A tear-off portion of the label containing information on the contents of the medication bottle was removed from the container at administration of drug to the subject and was to be opened for emergency purposes only. Patients took 1 or 2 tablets and an equivalent number of capsules every 4 to 6 hours as needed for pain, not to exceed 10 tablets and 10 capsules daily; patients >75 years of age were limited to 8 tablets and 1432

8 capsules daily. Ibuprofen (400 mg every 4 to 6 hours as needed) was permitted as rescue medication.

Efficacy and Safety Outcomes Several measures of efficacy were reported for each patient. At weekly intervals (days 1, 8, 15, and 22), patients were observed for 6 hours after receiving a dose of study medication; no supplemental analgesics were permitted during this observation period. Patients reported pain relief (0 = none; 1 = a little; 2 = some; 3 = a lot; 4 = complete) and pain intensity (0 = none; 1 = mild; 2 = moderate; 3 = severe) 30 minutes and 1, 2, 3, 4, 5, and 6 hours after the dose using Likert scales (Table I). Maximum pain relief was derived from the hourly pain relief scores. After each visit, and again at completion of the double-blind phase, patients provided a global assessment of efficacy of study medication using a Likert scale (1 = poor; 2 = fair; 3 = good; 4 = very good; 5 = excellent). Investigators used the same scale to assess overall efficacy in each patient at the completion of the double-blind phase. Additional efficacy data were derived from each patient's diary of studydrug and rescue-medication use. Medical history was taken at baseline, and physical examination and clinical laboratory values (hematology, blood chemistry, and urinalysis) were recorded both before and after the study. Vital signs (blood pressure, pulse rate, and body weight) were recorded at weekly visits. Blood pressure was recorded with the patient seated after 10 minutes of rest. Patients reported all adverse events, regardless of possible association with the study medication, either spontaneously or in response to general nondirected question-

W.S. MULLICAN AND J.R. LACY

Table I. Pain and efficacy Likert scales.

Pain intensity Pain relief* Patient/investigator assessment of efficacy

0

1

2

3

4

None None

Mild A little

Moderate Some

Severe A lot

Complete

Poor

Fair

Good

Very good

5

Excellent

*Same scale used for maximum pain relief over 6 hours.

ing. Adverse events that emerged or worsened after initiation of drug therapy were judged to be treatment-related.

Statistical Analysis Three summaries of patient-reported data were performed for analysis. Total pain relief (TOTPAR) was determined from the hourly pain relief (PAR) scores at each visit. The sum of the pain intensity differences (SPID) for each visit was derived from hourly pain intensity differences (PID), which in turn were calculated by subtracting pain intensity at each time point from the pain intensity reported at baseline. Adding the hourly PAR and PID scores yielded a single hourly score, pain relief and intensity difference (PRID). Finally, the hourly PRID scores were added into a weekly sum of pain relief and intensity difference (SPRID) score. For all summary scores, pain intensity and relief at 30 minutes and 1 hour were averaged to obtain hour 1 scores for each patient. Patients recorded their daily doses of study medications, and weekly mean and maximum doses were determined from these diaries. The ratio of mean daily doses was calculated to determine the relative potencies of the treatments.

The determination of sample size was based on clinical experience with tramadol, rather than on formal power calculation. Efficacy analyses were performed on an intent-to-treat population, using the last-observation-carried-forward method. Summary efficacy statistics considered all patients with study medication dosing information. Means and SDs were calculated for all efficacy variables. The difference was calculated between treatment groups for TOTPAR, SPID, and SPRID; 95% CIs were determined for each of these values. The 2 treatments were considered to have comparable efficacy when the upper and lower bounds of the 95% CI for the difference in summary efficacy scores were <10% of the maximum possible score (ie, _+2.4 for TOTPAR or SPID and _+4.8 for SPRID). Adverse-event summaries were based on treatment-emergent adverse events (ie, new or aggravated after treatment). Incidence summaries of these data by body system, preferred term, and included term were provided. P values for adverse events were based on the normal approximation to the difference of binomial proportions without the continuity adjustment. Summary safety statistics for potential treatment-related changes in hematologic, blood chemistry, or urinary tests also were calculated. 1433

CLINICAL THERAPEUTICS®

Table II. Baseline demographic characteristics of patients receiving tramadol/acetaminophen (TRAM/APAP) 37.5 mg/325 mg or codeine/acetaminophen (COD/APAP) 30 mg/300 mg. TRAM/APAP (n = 309)

COD/APAP (n = 153)

117 192

59 94

Sex

Male Female Age, y, mean -+ SD

56.2 _+ 13.7

60.4 _+ 13.6

Type of pain, no. (%) Low back Osteoarthritis Both

75 (24) 109 (35) 125 (40)

37 (24) 53 (35) 63 (41)

Baseline pain, no. (%)* None Mild Moderate Severe Missing

1 (<1) 65 (21) 186 (60) 50 (16) 7 (2)

0 (0) 32 (21) 86 (56) 32 (21) 3 (2)

Type of osteoarthritis, no. (%) Total Knee Hip Cervical spine Lumbar spine Hand Other

234 (100) 150 (64) 69 (29) 65 (28) 124 (53) 75 (32) 66 (28)

116 (100) 78 (67) 37 (32) 30 (26) 60 (52) 41 (35) 34 (29)

*Scale: 0 = none; 1 = m i l d ; 2 = moderate; 3 = severe.

RESULTS In accordance with the study protocol, of the 462 patients randomly assigned to treatment and assessed for tolerability, 309 patients (67%) were assigned to the tramadol/ APAP group and 153 (33%) to the codeine/ APAP group. Dosing information was not available for 3 patients; therefore, 459 patients were assessed for efficacy. Baseline demographic characteristics of the 462 patients randomly assigned to the 2 treat1434

ment arms are shown in Table II; these characteristics were comparable between groups. The mean age of patients was 57.6 years (range, 22-91 years), with 112 (24%) reporting chronic nonmalignant low back pain, 162 (35%) reporting OA pain, and 188 (41%) reporting both. Of the 350 patients with OA pain, the knee (228 patients, 65%) and the lumbar spine (184 patients, 53%) were the most common locations.

W.S. MULLICAN AND J.R. LACY

Table III. Study completion/withdrawal information for patients receiving tramadol/acetaminophen (TRAM/APAP) 37.5 mg/325 mg or codeine/acetaminophen (COD/APAP) 30 rag/300 mg.

Randomized, no. Completed, no. (%) Withdrew, no. (%) Adverse events Subject choice Follow-up Other

TRAM/APAP

COD/APAP

Total

309 248 (80) 61 (20) 37 (12) 14 (5) 4 ( 1) 6 (2)

153 121 (79) 32 (21) 21 (14) 5 (3) 2 ( 1) 4 (3)

462 369 (80) 93 (20) 58 (13) 19 (4) 6 (1) 10 (2)

Eighty percent (248/309) of the subjects in the tramadol/APAP group and 79% (121/153) in the codeine/APAP group completed the study (Table III). Discontinuation rates were similar between the 2 groups for each category (eg, adverse events, subject choice). Both groups demonstrated >95% compliance (ie, patients took an equal number of tablets and capsules and did not exceed the maximum dose). Mean TOTPAR scores were comparable between the 2 groups at each weekly observation (Table IV, Figure 1). On day 1, patients reported pain relief within 30 minutes that increased until hour 2 and then reached a relative plateau for at least 6 hours in both groups (Figure 2). On day 22, mean hourly PAR values continued to be similar for tramadol/APAP and codeine/APAR Mean SPID scores were similar for tramadol/APAP and codeine/APAP at each visit (Table IV). Hourly PID values were similar from the first day of the study until the last visit and remained comparable between the 2 study medications (Figure 3).

Combining pain relief and intensity into PRID scores produced similar results for a dose of tramadol/APAP or codeine/APAE When hourly scores were further summed (SPRID), the 2 treatments were again comparable at each visit (Figure 4). Throughout the study, patients taking either tramadol/APAP or codeine/APAP reported comparable maximum pain relief over 6 hours, with a mean score at every report between 2 (some pain relief) and 3 (a lot of pain relief). Maximum pain relief was "a lot" or "complete" for >40% of tramadol/APAP- and codeine/APAP-treated patients each week and for 50% of tramadol/ APAP-treated patients at the final visit (day 22). More than 50% of the patients in both groups assessed the efficacy of each treatment as good, very good, or excellent every week. Mean assessment scores were similar throughout the study for the 2 treatments; they ranged from 2.6 to 3.0, with a median rating of 3 (good) for both drugs at each visit. At the completion of the double-blind phase of therapy, 32% (95/ 298) of patients rated tramadol/APAP efficacy as very good or excellent, compared 1435

CLINICAL THERAPEUTICS ®

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Figure 1. Mean total pain relief (TOTPAR) scores determined from hourly pain relief scores at each visit. Scale for hourly pain relief: 0 = none; 1 = a little; 2 = some; 3 = a lot; 4 = complete. TOTPAR scores could range from 0 to 24. APAP = acetaminophen.

with 29% (43/147) of patients for codeine/ APAE Investigators rated tramadol/APAP efficacy as very good or excellent in 32% of patients (94/298) compared with 30% (45/148) for codeine/APAP. Mean overall scores were comparable for both patient assessments (2.9 + 1.14 for tramadol/APAP and 2.9 + 1.13 for codeine/APAP) and investigator assessments (3.0 _+ 1.11 and 2.9 _+ 1.11, respectively). The mean double-blind daily dose was 3.5 tablets and capsules in both groups (mean daily doses of tramadol/APAP: 131 mg/1133 mg, range, 3-365 mg/28-3160 mg; codeine/ APAP: 105 mg/1054 mg, range, 9-253 mg/ 86-2534 mg). When the ratio of mean daily doses for tmmadol/APAP and codeine/APAP were compared, the relative potency of the 2 treatments was 0.99 overall. The maximum number of tablets or capsules required in a single day for pain relief was a mean of 5.5 tablets of tramadol/ APAP and 5.7 capsules of codeine/APAP.

The percentage of patients using supplemental ibuprofen at any point during the study was comparable between the 2 groups and ranged from 21% to 30% for each week of the study. The mean duration of therapy was 25.5 days for tramadol/APAP and 25.0 days for codeine/APAP. The overall rates of treatment-emergent adverse events were comparable for the 2 groups (Table V); 71% of the tramadol/APAP-treated patients and 76% of the codeine/APAP-treated patients reported adverse events. Serious adverse events were not associated with either therapy. One patient was hospitalized for chest pain after the first dose of tramadol/APAP, but the chest pain did not occur when the patient restarted tramadol/APAP therapy, and a relationship to the study medication was deemed unlikely by the investigator. Somnolence (24% [37/153]) and constipation (21% [32/153]) were significantly more common in the codeine/APAP group 1437

CLINICAL THERAPEUTICS®

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Figure 2. Mean hourly pain relief scores (0 = none; 1 = a little; 2 = some; 3 = a lot; 4 = complete), days 1 and 22. APAP = acetaminophen. than in the tramadol/APAP group (17% [54/309] and 11% [35/309], P = 0.05 and P < 0.01, respectively). In all, 37 patients (12%) discontinued tramadol/APAP therapy because of an adverse event compared with 21 patients (14%) in the codeine/ APAP group; few of these adverse events were unexpected for the given medication. Symptoms possibly related to allergic reactions were reported by 8% (26/309) of tramadol/APAP patients and 8% (12/153) of codeine/APAP patients. Most reactions in both groups were reports of either rash (13/38) or pruritus (17/38), which were mild and not treatment limiting. Neither group had clinically significant mean changes (>5% change) for any laboratory values from baseline to completion of the study. Eleven patients taking tramadol/APAP experienced an increase in liver enzymes (on liver function tests) 1438

from normal to above-normal values, but an equal number of patients had elevated results on liver function tests before the study that resolved during tramadol/APAP therapy. Two patients in each group (0.6% tramadol/APAP vs 1.3% codeine/APAP) had markedly abnormal alanine aminotransferase levels (98 and 80 mg/dL for tramadol/APAP and 110 and 220 mg/dL for codeine/APAP) during 4 weeks of treatment. There were no signs of abuse attributed to either therapy. Power analyses were performed for the summary efficacy scores and adverseevent data, and maximum possible SDs were used in each power calculation. Assuming the 2 groups had identical efficacy, the probability that each 95% CI would fall within -2.4 to 2.4 for TOTPAR and SPID and within -4.8 to 4.8 for SPRID was nearly 100% for each vari-

W.S. MULLICAN AND J.R. LACY

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Figure 3. Mean hourly pain intensity difference scores, days l and 22, determined by subtracting pain intensity at each time point from pain intensity at baseline. Scale for pain intensity: 0 = none; 1 = mild; 2 = moderate; 3 = severe. APAP = acetaminophen. able at each time point. For adverse events, assuming the true underlying difference in incidence rates was 10%, the power of rejecting the null hypothesis of equal incidence rates exceeded 97%. DISCUSSION In this study, tramadol/APAP 37.5 mg/325 mg combination tablets had comparable efficacy to codeine/APAP 30 mg/300 mg combination capsules. A single dose of tramadol alone has been shown to provide pain relief within 1 hour that continues for at least 6 hours. 44 Pain relief has been recorded within 30 minutes in clinical studies of APAE 45'46 In single-dose studies, tramadol/APAP had superior efficacy to tramadol or APAP alone and faster esti-

mated onset of action (17 minutes) compared with tramadol alone (51 minutes). 43 Therefore, it is not surprising that tramadol/ APAP provided pain relief within 30 minutes that lasted for at least 6 hours during each visit in this study. The efficacy of tramadol/APAP or codeine/ APAP was assessed as good, very good, or excellent by more than half the patients at weekly clinic visits. At the conclusion of the 4-week, double-blind phase of this study, the overall efficacy of tramadol/ APAP was rated by patients and investigators as very good or excellent in 32% of cases; the ratings were similar for codeine/APAP. Patients used a mean of 3 to 4 doses daily and a maximum of 5 to 6 doses daily for each treatment, correlating to a mean 1439

CLINICAL THERAPEUTICS+

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Figure 4. Mean hourly pain relief and intensity difference scores, days 1 and 22, determined by adding the hourly pain relief scores (0 = none; 1 = a little; 2 = some; 3 = a lot; 4 = complete) and the pain intensity difference scores (difference at each time point in pain intensity scores [0 = none; 1 = mild; 2 = moderate; 3 = severe] from baseline). APAP = acetaminophen.

daily tramadol/APAP dose of 131 mg/1133 mg and a mean daily codeine/APAP dose of 105 mg/1054 mg. When mean daily doses of tramadol/APAP and codeine/APAP were compared, the relative potency was 0.99. The use of supplemental analgesia was the same for both treatments. Overall, tramadol/APAP and codeine/APAP provided comparable pain relief with the same dosing regimen (1 to 2 tablets or capsules every 4 to 6 hours as needed for pain). Although the absence of a placebo group in this study raises the possibility that neither treatment was more effective than placebo, tramadol alone has previously been shown to relieve low back 1440

pain 3° and OA pain 28 more effectively than placebo, as have APAP 47-49 and codeine/ APAP.5°,51 Furthermore, in 3 studies of dental pain, tramadol/APAP was significantly more effective than placebo. 43 Another potential limitation of this study was that 21% of the patients had mild pain: 1 patient reported no pain at baseline. As a result, these patients were less likely to demonstrate pain relief or intensity changes on the scales used, which may have reduced the apparent efficacy of the 2 treatments. Starting with tramadol 25 mg and titrating doses over 10 to 16 days has been shown to improve tolerability compared with more rapid titration with tramadol

W.S. MULLICAN AND J.R. LACY

Table V. Most common treatment-emergent adverse events.*

Somnolence Nausea Dizziness Constipation Headache Vomiting Diarrhea Dry mouth Fatigue Dyspepsia Any adverse event

Tramadol/Acetaminophen (n = 309)

Codeine/Acetaminophen (n = 153)

P

54 (17) 53 (17) 47 (15) 35 (11) 34 (11) 22 (7) 19 (6) 16 (5) 15 (5) 14 (5) 220 (71)

37 (24) 29 (19) 21 (14) 32 (21) 11 (7) 10 (7) 7 (5) 10 (7) 9 (6) 8 (5) 117 (76)

0.05 0.32 0.33 <0.01 0.08 0.41 0.23 0.28 0.33 0.37 0.11

*Reported by >5% of subjects in either treatment group. Data reported as number (%) of patients.

50 mg, 4° so the use of a lower dose of tramadol (37.5 rag) in a tramadol/APAP combination tablet may improve tolerability relative to tramadol 50 mg. In this study, the overall tolerability profile was comparable between tramadol/APAP and codeine/APAP, with similar incidences of adverse events and drug discontinuation. Adverse events reported were not serious; they reflected the established adverse-event profiles for the study medications. Headache was more common in the tramadol/APAP group, whereas patients taking codeine/APAP reported constipation and somnolence more frequently. Constipation (a c o m m o n problem with opioids) may be serious if inadequately treated. 52 Although seizures have been reported in patients receiving tramadol, particularly those with a decreased seizure threshold, 53 no seizures were observed during this study. However, patients taking medications known to reduce the seizure threshold were excluded from this study, so the tolerability and efficacy pro-

file of tramadol/APAP in this population remains to be determined. Tramadol has been shown to have a low potential for abuse or dependence with l o n g - t e r m use. 37 Physical dependence and tolerance are physiological responses to the continued use of pure Ix-agonist opioid drugs such as codeine, and they should not be confused with psychological addiction or drug abuse. Physical tolerance may rarely lead to decreased efficacy with continued therapy or withdrawal symptoms on discontinuation) 4,55 However, there were no signs of abuse or dependence in either group in this study. CONCLUSIONS A tramadol/APAP (37.5 mg/325 mg) combination tablet or codeine/APAP (30 mg/ 300 mg) combination capsule provided equal pain relief from chronic nonmalignant low back pain, OA pain, or both by 30 minutes after each dose. Patient reports of pain relief and pain intensity were 1441

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comparable for the 2 products, as were patient and investigator assessments of efficacy. Tramadol/APAP and codeine/APAP were equipotent and associated with a similar overall incidence of adverse events, but tramadol/APAP was less likely to be associated with constipation or somnolence. Based on the results of this study, in appropriate patients, tramadol/APAP offers similar efficacy and dosing but is better tolerated than codeine/APAP. ACKNOWLEDGMENTS This research was supported by the R.W. Johnson Pharmaceutical Research Institute and Ortho-McNeil Pharmaceutical, Inc, Raritan, New Jersey. The authors thank Jonathan Latham for editorial assistance and Roseanne Lane and Julia Wang for statistical assistance. Members of the TRAMAP-ANAG-006 Study Group include Donna J. Adamoli, MD, Philadelphia, Pennsylvania; Lawrence K. Alwine, DO, Downingtown, Pennsylvania; Victor Biton, MD, Little Rock, Arkansas; Michael H. Bourne, MD, Salt Lake City, Utah; Selwyn A. Cohen, MD, Trnmbull, Connecticut; Harmon H. Davis II, MD, Cheyenne, Wyoming; C. Andrew DeAbate, MD, New Orleans, Louisiana; Robin K. Dore, MD, Anaheim, California; Keith R. Edwards, MD, Bennington, Vermont; Luis R. Espinoza, MD, New Orleans, Louisiana; Alan B. Fishman, MD, Atlanta, Georgia; Roy M. Fleischmann, MD, Dallas, Texas; Richard G. Free, MD, Hartford, Connecticut; Alan Graft, MD, Ft. Lauderdale, Florida; Everett G. Heinze, MD, Austin, Texas; Michael D. Hoffstetter, MD, Alexandria, Virginia; Paul E Howard, MD, Paradise Valley, Arizona; Rita Jain, MD, Manhasset, New York; Richard A.H. Jimenez, MD, Edmonds, Washington; Louis 1442

C. Kirby II, MD, Sun City, Arizona; Jean Korchinski, MD, Forest Grove, Oregon; Joseph R. Lacy, MD, Palo Alto, California; Craig F. LaForce, MD, Raleigh, North Carolina; Steven Lamberson, MD, Marshfield, Wisconsin; Paula J. Lane, MD, Albuquerque, New Mexico; David T. Lee, MD, Indianapolis, Indiana; Clark D. McKeever, MD, Houston, Texas; Larry W. Moreland, MD, Birmingham, Alabama; William S. Mullican, MD, Evansville, Indiana; Kenneth Niejadlik, MD, Denver, Colorado; Dianne Petrone, MD, Dallas, Texas; Bryan Pogue, MD, Boise, Idaho; Jeffrey E. Poiley, MD, Orlando, Florida; Martin Posner, MD, Great Neck, New York; Anthony D. Puopolo, MD, Milford, Massachusetts; Harvey Resnick, MD, Lake Jackson, Texas; Thomas J. Schnitzer, MD, PhD, Chicago, Illinois; Harry M. Serfer, DO, Hollywood, Florida; David R. Silvers, MD, Metairie, Louisiana; Eric S. Solomon, MD, Birmingham, Alabama; William J. Stein, MD, Rochester, New York; M. Dale Terrell, MD, St. Louis, Missouri; John R.E Tesser, MD, Phoenix, Arizona; Muhammad B. Yunus, MD, Peoria, Illinois; John J. Zuzga, Jr, DO, Chicago, Illinois. REFERENCES The Gallup Organization. Pain in America: Highlights from a Gallup survey. May 21-June 9, 1999. Available at: http://www. arthritis.org/conditions/speakingofpain/ factsheet.asp. Accessed September 4, 2001. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States.Arthritis Rheum. 1998;41: 778-799. 3. Borenstein D. Epidemiology, etiology, diagnostic evaluation, and treatment of low

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Address correspondence to: William S. Mullican, MD, 401 Professional Boulevard, Evansville, IN 47714.

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