Tramadol produces modest results—or none at all
The tramadol review10 included 11 randomized controlled trials (RCTs) with a total of 1019 participants who took tramadol or tramadol/acetaminophen (paracetamol) and 920 controls. In 6 of the 11 studies, the controls received placebo; the remaining 5 trials used “active controls,” with the control group for each RCT receiving a different analgesic. (To learn more about the methodology, see “How the reviews were conducted”.)
Placebo-controlled trials. Compared with patients on placebo, those receiving tramadol had an average absolute reduction in pain of 8.5 mm on a 0-100 mm visual analog scale (VAS) (95% confidence interval [CI], -12.05 to -4.9). That small benefit, however, did not reach the level defined as the minimal perceptible clinical improvement—a reduction of 9.7 mm on Western Ontario and McMaster Universities (WOMAC)’s OA pain subscale.12
Active-controlled trials. In the 5 RCTs comparing tramadol with another active agent, tramadol proved to be no better than the control drug. In fact, in a study of tramadol vs acetaminophen, 500 mg acetaminophen 3 times a day provided more pain relief than 50 mg tramadol 3 times a day.13 Although this was a small (N=20), short-term (7-day) study, this finding is notable because participants took less than the usual acetaminophen dose of 1 g up to 4 times a day.
Nor was tramadol superior to the agents it was compared with in the 4 other active-controlled trials—dihydrocodeine,14 dextropropoxyphene,15 pentazocine,16 and diclofenac17—in reducing pain intensity. It is important to keep in mind, however, that in each of these studies, both the quantity and quality of the evidence was limited. (Two studies did not use numerical scales,14,16 for example; all had methodological issues; and none lasted longer than 28 days.)
How the reviews were conducted
The Cochrane Musculoskeletal Group conducted a review of tramadol and a review of other oral opioids and transdermal fentanyl for the treatment of osteoarthritis (OA). Both reviews featured pain, function, and safety as primary outcomes. The tramadol review included randomized controlled trials (RCTs) for OA in any joint, while the oral and transdermal opioid review included randomized and quasi-randomized trials of treatment for OA of the hip or knee. Other parameters follow:
The tramadol review included 11 RCTs, with a total of 1019 participants receiving either tramadol alone or tramadol/acetaminophen (paracetamol) and 920 controls. In 6 of the 11 studies, the controls received placebo; the remaining 5 studies featured “active control.” That is, the control groups received acetaminophen 500 mg 3 times daily, diclofenac (25-50 mg up to 3 times daily on demand), dihydrocodeine 60 mg twice daily, dextropropoxyphene 100 mg 3 times daily, or pentazocine 50 mg 4 times per day. Because each of these agents was used in only one trial, the reviewers could not reach definitive conclusions about tramadol’s performance relative to other medications. The average number of participants in the tramadol and control groups was 91 and 80, respectively. The average length of follow-up was 35 days.
The 11 RCTs included in this review used a variety of pain scales to assess the results of tramadol, active control medications, and placebo. For comparative purposes, the reviewers pooled the results from studies that used numerical scales (0 to 100 and 0 to 10) to assess pain intensity. As a reference, we have used 9.7 and 9.3, respectively, determined by other researchers to be the minimal perceptible clinical improvements on the Western Ontario and McMaster Universities (WOMAC) pain and physical function 0-100 mm visual analog scales.12
The review of oral and transdermal opioids included 10 studies, with a total of 1541 patients receiving opioids and 727 receiving placebo.17 There were 3 trials of codeine (in 2 of the 3, a simple analgesic [acetaminophen 3000 mg/d or ibuprofen 1200 mg/d] was co-administered to both the treatment and control groups); other opioids included in the trials were oxycodone (4 trials), oxymorphone (2 trials), morphine (1 trial), and transdermal fentanyl (1 trial).
A modest boost in well-being
The reviewers measured function in 2 ways, focusing on both global improvement and improvement in physical function.
Global assessment. For the global assessment, the reviewers defined a treatment response as achieving at least a moderate improvement. By that standard, tramadol may improve overall well-being more than placebo. In the placebo-controlled trials, the number needed to treat (NNT) to elicit one treatment response was 6.
Three of the trials with active controls included global/functional assessments, and the results—bearing in mind the reduced quality and quantity of the evidence—were mixed. In a comparison of tramadol with dextropropoxyphene, tramadol increased the likelihood of moderate improvement by 38% (relative risk, 1.38 (95% CI, 1.15-1.67).10 In a trial of tramadol vs pentazocine, tramadol was more effective in reducing the duration of morning stiffness (by about 10 minutes), but not its severity. Tramadol was comparable with pentazocine in the 7 other measures of OA and function.16 In the tramadol-diclofenac study, both drugs were equally effective.17