For nearly half a century, tramadol has been used as a pain reliever. It is not perfect, no analgesic is, but it has helped millions upon millions of patients with chronic pain. That is why recent headlines declaring tramadol “less effective” and “more risky” caught my attention. These stories were based on a single meta-analysis, which concluded that this medication offers “limited analgesic benefits” and that its harms, especially cardiac-associated harms, “likely outweigh” its effectiveness.

Yet when I read the actual paper, the supplementary data, and several research articles it summarized, I found something very different: overstated conclusions, misinterpretation of placebo effects, and a statistical artifact. Unfortunately, those nuances were lost as media outlets amplified the most dramatic claims without deeper scrutiny.

This is how an echo chamber forms, and how it can mislead clinicians, policy makers, and patients.

Effectiveness: what the original studies actually showed

The meta-analysis evaluated 13 placebo-controlled trials and concluded that tramadol provides only “limited benefits.” Yet in every single one of those trials, the original investigators concluded the opposite: Tramadol was effective and safe for the chronic pain condition under study. Representative outcomes of those trials follow:

• 80 percent of tramadol-treated patients improved vs. 69 percent on placebo.
• 44.7 percent of tramadol-treated patients improved vs. 23.9 percent on placebo.
• 77 percent of tramadol patients reported moderate to complete pain relief vs. 50 percent on placebo.
• Clinical improvement averaged 16.6 percent greater with tramadol than placebo.
• 45.8 percent of tramadol-treated patients satisfied or highly satisfied vs. 33 percent on placebo.
• Patients’ assessment positive: global efficacy, 77.6 percent of the tramadol group versus 59.8 percent on placebo.

Using their own criteria, the researchers calculated tramadol’s effectiveness as 48.6 percent with a placebo effect of 41.1 percent, a difference of only 7.5 percent benefit over placebo, far lower than some of the original studies’ results. Thus it is difficult to reconcile this new analysis with those of the authors who actually did the research and the patients whose pain was effectively relieved. However, based solely on their calculation of tramadol’s substantial placebo effect, the study concluded that it had “limited analgesic benefits.”

The authors misinterpret the importance and role of the placebo effect. Tramadol, like other analgesics, has a substantial placebo response. The placebo effect in pain trials is well-established and biologically meaningful. It does not cancel out the medication’s effect; they coexist. It is their cumulative effect that is important. The placebo effect is not a failure or a short-coming of the medication.

Over several decades of research, tramadol has consistently shown statistically significant pain reduction compared with placebo. This is nothing new. This is the standard by which all analgesics, including other opioids, acetaminophen, and NSAIDs, are evaluated.

Pharmacogenetics matter

Tramadol is a prodrug. It must be metabolized via CYP2D6 to its active metabolite, M1. Patients who are poor or intermediate metabolizers (up to 50 percent in some populations) may experience less benefit. This is not a flaw of the medication; it is a known, predictable pharmacogenetic reality. Online patient reports reflect this variability. Among user reviews, many chronic pain patients report positive experiences with tramadol, similar to oxycodone and combination oxycodone products, though lower than morphine or hydromorphone.

For patients who do not respond well to tramadol, the solution is straightforward: select a different analgesic. Curtailing or banning tramadol prescriptions for the sizable percent of patients who do find it effective for pain management is not a reasonable course of action.

Tramadol is certainly not universally effective. No analgesic is. But the claim that it is “ineffective” is incompatible with the evidence base.

Safety: the “harm signal” that wasn’t

The Times of India headline emphasized an alarming claim: tramadol “doubles the risk of heart problems.” That claim came from a highly aggregated analysis of rare serious adverse events (SAEs). But when one examines the actual numbers, a very different picture emerges.

Here is the raw data from the supplementary materials:

Cardiac-related SAEs (all studies combined):

• Tramadol: 12 events out of 1,786 patients (0.67 percent)
• Placebo: 2 events out of 858 patients (0.23 percent)

A two-sided Fisher’s exact test reveals p = 0.25 (not statistically significant).

Moreover:

• Ischemic stroke did not occur in the tramadol arm at all.
• Deep vein thrombosis occurred once with tramadol and once with placebo.
• Congestive heart failure occurred once, and the study authors explicitly stated it was not related to tramadol.
• Aortic aneurysm occurred only once.
• Chest pain and syncope (fainting), two of the seven events, are already known, rare adverse effects of tramadol.

Coronary artery disease (CAD) was the most common event (four cases). But in the U.S. population, about 6.7 percent of adults have CAD, far higher than the 0.45 percent seen in the tramadol group. In other words, these rare occurrences are entirely compatible with background population risk.

Even the meta-analysis authors acknowledge that none of the individual adverse events reached statistical significance. Only when they were pooled with additional non-cardiac events, and then subjected to beta binomial regression, did a statistical “signal” appear. This is a classic situation in which statistical aggregation of rare events, not biology, creates the appearance of risk.

The echo chamber takes over

Despite the marginal data, the media response was overwhelming: 113 news reports, 8 blogs, 66 X reposts. Many news accounts used identical headlines and similar or identical talking points from a BMJ press release, uncritically reiterating and sometimes exaggerating the authors’ conclusions.

Unfortunately, clinicians who review these headlines may hesitate to prescribe tramadol, a medication that is effective and appropriate for many patients. Policymakers may cite the study to further restrict opioid prescribing, despite continued evidence that prescription opioids taken as directed are not driving overdose deaths (illicit fentanyl is).

What gets lost is the nuance: tramadol is helpful for many, not all, patients and like all medications, it carries risks. But the data do not support the claim that its harms outweigh its benefits.

John A. Bumpus is a professor emeritus of chemistry and biochemistry.