Only higher-dose tramadol outperforms placebo for improved pain, function in knee, hip OA – Healio

Zhang X, et al. Arthritis Care Res. 2021;doi:10.1002/acr.24750.
Zhang X, et al. Arthritis Care Res. 2021;doi:10.1002/acr.24750.
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.”
“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duplicates and other articles that failed to meet criteria, six randomized controlled trials — five published and one unpublished, representing 3,611 total participants — were included in the analysis.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.”
David A. McLain, MD, FACP, FACR
Slowly but surely, the treatment options are shrinking for painful osteoarthritis. NSAIDs have been our standard, yet nephrologists, gastroenterologists and cardiologists are now frequently telling our patients to stop these medications because they are harmful. Another issue is the interference of the beneficial cardiovascular effects of aspirin by the two most common OTC NSAIDs: ibuprofen and naproxen.
Acetaminophen provides some relief and for a number of our patients, it is often all they need. Liver toxicity is a concern with acetaminophen and the FDA has set the limit at 4000 mg per day with Tylenol manufacturer, McNeil, lowering their recommended limit to 3250 mg per day. Propoxyphene, which was a staple of osteoarthritis pain relief from the mid-1970s, was removed from the market in 2010 for its effect on the QT interval and high overdose potential. Many of the propoxyphene patients were then switched to tramadol or hydrocodone.
We see from this article that the effect of tramadol only exceeds placebo at 300 mg per day and even at this dosage, this effect was very small. Tramadol adverse effects (gastrointestinal and central nervous system) increase with dosage, as the authors noted; seizures, hypoglycemia, and serotonin syndrome also occur with tramadol.
Then, there are the patients who were switched to hydrocodone, which was made a schedule II narcotic in 2014. Subsequently, the opioid crisis has curtailed the use of narcotics and many of these patients, who were unable to taper, have been assigned to a pain clinic. There is a real need in rheumatology and medicine, for new effective treatments for painful osteoarthritis that are also safe and nonaddictive.
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