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Disclosures: The researchers report funding from National Natural Science Foundation of China, the National Key Research and Development Project, and the Key Research and Development Program of Hunan Province.
July 29, 2021
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Only higher-dose tramadol outperforms placebo for improved pain, function in knee, hip OA

Disclosures: The researchers report funding from National Natural Science Foundation of China, the National Key Research and Development Project, and the Key Research and Development Program of Hunan Province.
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A daily 300 mg dose of tramadol — but not 100 or 200 mg doses — surpassed placebo in improving pain and function related to hip or knee osteoarthritis, but was linked to increasing adverse events, researchers noted in Arthritis Care & Research.

“It was reported that the prescription for tramadol had increased by 22.8% from 2012 to 2015 in the USA,” Xiurui Zhang, MD, of Xiangya Hospital, Central South University, in Changsha, China, and colleagues wrote. “For OA patients, tramadol was most commonly prescribed as the first option of the opioid drug (39.7%). Despite the widespread use, concerns were raised about the efficacy and safety of tramadol used in OA patients. Multiple harms have been reported in association with the prescription of tramadol, including nausea, dizziness, somnolence, and headache, serotonin syndrome, myocardial infarction (MI) and mortality recently.”

Tramadol 300 mg daily demonstrated minimal improvement in pain and function related to hip or knee OA, and is linked to increasing adverse events, compared with placebo, according to data derived from Zhang X, et al. Arthritis Care Res. 2021;doi:10.1002/acr.24750.

“Additionally, though generally considered a weak opioid, there is an increased awareness of the risks of dependence associated with tramadol,” they added. “Until now, there is a paucity of data on the dose comparative efficacy and safety of tramadol that builds on the totality of randomized trial evidence, which is however necessarily required for making trade-off decisions between better pain relief and higher toxicity for both clinicians and patients.”

To assess the safety and efficacy of tramadol in hip or knee OA, Zhang and colleagues conducted a systematic literature review and metal-analysis. The researchers reviewed Pubmed, Embase, the Cochrane Library and Web of Science from inception to May 2020 for randomized controlled trials that compared 100-, 200- and 300-mg daily doses of tramadol, as well as placebo, in patients with knee or hip OA. Other inclusion criteria included reporting pain, function or adverse-event outcomes.

The initial search netted 1,327 records. However, after excluding duplicates and other articles that failed to meet criteria, six randomized controlled trials — five published and one unpublished, representing 3,611 total participants — were included in the analysis. The researchers measured pain and function at, or nearest to, 12 weeks for efficacy. Regarding safety, Zhang and colleagues measured gastrointestinal, cardiovascular and central nervous system adverse effects, as well as withdrawals.

According to the researchers, the 100- (SMD = –0.16; 95% CI, –0.34 to 0), 200- (SMD = –0.21; 95% CI, –0.37 to –0.06) and 300-mg (SMD = –0.3; 95% CI, –0.48 to –0.14) daily tramadol doses were statistically more effective than placebo in pain relief. However, only the 300 mg dose was superior to placebo for improving function (SMD = –0.24; 95% CI, –0.47 to –0.03).

Moreover, the 100- (RR = 2.29; 95% CrI, 1.22-4.25), 200- (RR = 4.35; 95% CrI, 2.31-8.01) and 300- mg (RR = 6.02; 95% CrI, 3.22-11.1) daily doses were associated with a higher risk for gastrointestinal adverse effects. Tramadol 100 to 300 mg per day similarly demonstrated higher risks for central nervous system adverse effects and withdrawals. The risk for cardiovascular effects remained unclear.

“The findings of this meta-analysis indicated that a high dose of tramadol (300 mg/day) was associated with statistically better effects on both pain relief and functional improvement compared with placebo for knee or hip OA,” Zhang and colleagues wrote. “However, the difference was of uncertain clinical importance.”

“In addition, all three doses of tramadol involved an increased risk of gastrointestinal and [central nervous system] AEs compared with placebo, and the risk was more pronounced in the high-dose group,” they added. “Therefore, recommending tramadol for a chronic disease like knee or hip OA may not be sufficiently supported by the presented evidence.”