According to Drugs.com tramadol is an opioid agonist used to treat moderate to moderately severe chronic pain in adults, including postoperative pain. Wikipedia said tramadol was patented in 1977 by a West German pharmaceutical company. In the mid 1990s it was initially approved as a non-controlled substance in the U.S., but then became a Schedule IV Controlled Substance in 2014. It has about one-tenth the potency of morphine, and is widely seen as a safer option for chronic pain. In 2023 it was the 36th most commonly prescribed medication in the U.S., but a recent study concluded the potential harms associated with tramadol likely outweigh the risks.
The Danish study, “Tramadol versus placebo for chronic pain,” was published in BMJ Evidence-Based Medicine. Their analysis showed evidence of a beneficial effect of tramadol on chronic pain, but it did not meet their predefined level for clinical significance of pain relief. The researchers concluded that although tramadol had a slight effect on reducing chronic pain, it was also likely to increase the risk of serious and non-serious adverse effects. “The potential harms associated with tramadol use for pain management likely outweigh its limited benefits.”
A co-author of the study told Medpage Today that while tramadol is often perceived as safer than other opioids for the management of chronic pain, this view lacks supporting evidence. He thought the use of tramadol and other opioids should be minimized as much as possible. “Our study provides evidence in support of this recommendation.”
Nineteen clinical trials involving 6,506 participants with chronic pain were involved in the study. The age of the participants ranged from 47 to 69; their mean age was 58. All but one of the trials involved oral tramadol. Treatment ranged from 2 to 16 weeks, and follow-up was from 3 to 15 weeks. Eight trials assessed serious adverse events after follow-up periods that ranged from 7 to 16 weeks.
Serious adverse events in the tramadol groups included chest pain, coronary artery disease, congestive heart failure, prostate cancer, breast cancer, and thyroid neoplasm [a tumor that may or may not be malignant]. The follow-up period for neoplasms was short, making a causal link between tramadol and new cancer disease “questionable at this point,” the researchers noted.
Two trials that evaluated tramadol’s influence on quality of life found improvements, but three reported no significant differences between tramadol and placebo. The researchers acknowledged their study had several limitations, that likely overestimated the beneficial effects. “All included trials were at high risk of bias except two, which increases the likelihood that our findings overestimate the beneficial effects and underestimate the harmful effects of tramadol.”
A doctor and professor who has studied tramadol’s safety and effectiveness, but was not involved in the study, told Medscape Medical News the review stood out by its examination of tramadol’s use across a range of chronic pain conditions. She thought its findings add weight to the growing evidence that challenges perceived advantages over other analgesics. “This review doesn’t change the narrative but strengthens it: Tramadol’s reputation as a safer or uniquely effective opioid is increasingly difficult to defend.” She also noted the methodological shortcomings of many of the included trials. “Many outcomes that matter to patients — like quality of life, functional improvement, or withdrawal — were either inconsistently measured or not reported at all.”
Another professor and medical director of pain management at the Icahn School of Medicine at Mount Sinai in New York City thought the study provided evidence that tramadol increased the risk of serious adverse events. But its broad approach could also be a confounding factor. “Tramadol may benefit some conditions more than others,” and this could alter the overall risk-benefit profile. He said clinicians should consider the study alongside other research and their own experience when deciding whether or not to prescribe the drug.
He thought it was important to take the study into consideration, “but there are multiple studies that support the use of tramadol, and we have to look at the totality of the evidence.” Let’s not forget how we overestimated the beneficial effects of OxyContin (oxycodone) and underestimated its harmful effects, and repeat that mistake with tramadol. There is a lower abuse potential with tramadol than there is with oxycodone, but it’s still an opioid. See “Giving an Opioid Devil Its Due” and “The Sackler Cartel Goes Before the Supreme Court” for more on OxyContin and its influence on the opioid crisis.
With the U.S. opioid crisis evolving from prescription pain misuse to heroin, then to fentanyl and now possibly to nitazenes (see “Could Nitazenes Replace Fentanyl?”), concern with tramadol misuse may seem like majoring on a minor concern. But remember, the fentanyl problem emerged out of the misuse of prescription drugs. We don’t want to underestimate the misuse potential of tramadol. Medpage Today reported in 2019 that a large insurance claims study showed patients who used tramadol alone after surgery had higher risk of prolonged opioid use.
If tramadol really is very different from other opioids we give people for acute pain, we might expect to see differences in long-term use of opioids in people who are prescribed tramadol versus other opioids after surgery. . . We found the opposite was true; people who got tramadol rather than oxycodone or hydrocodone after their surgery were actually more likely to continue using opioids long-term.
The study, “Cohort use of tramadol after acute pain episode,” said tramadol carried a similar or somewhat greater risk of transitioning from acute to prolonged use when compared with other short acting opioids. The researchers thought from a standpoint of the risk of dependency, clinicians prescribing tramadol for acute pain should exercise a level of caution similar to that of other short acting opioids, i.e., oxycodone and hydrocodone. They suggested the DEA consider rescheduling tramadol “to a level that better reflects its risks of prolonged use.”
Recall that tramadol wasn’t classified as a Schedule IV Controlled Substance until 2014, some 20 years after it was initially approved by the FDA for use in the U.S. Schedule IV means it was thought to have a lower risk of abuse and dependence than schedule II opioids like oxycodone and hydrocodone. It does carry a boxed warning for addiction and abuse, and its medication guide warns of possible “psychic and physical dependence.” Tramadol can be associated with craving and tolerance. Withdrawal symptoms can occur if it is discontinued abruptly.
These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection [goosebumps] and rarely hallucinations. Clinical experience suggests that withdrawal symptoms may be relieved by reinstitution of opioid therapy followed by gradual, tapered dose reduction of the medication combined with symptomatic support.
ClinCalc.com listed tramadol as the 36th most prescribed U.S. medication in 2023 with 16,010,294 prescriptions. Hydrocodone ranked 25th with 21,506,768, and oxycodone ranked 49th with 13,502,066.
The Other Opioid Crisis
In December of 2019, the Associated Press (AP) published “How tramadol, touted as safer opioid, became 3rd world peril.” The AP said the world had been told tramadol was safer than OxyContin, Vicodin or the fentanyls that caused so much devastation in the U.S. “But now they are the root of what the United Nations named ‘the other opioid crisis’ — an epidemic featured in fewer headlines than the American one, as it rages through the planet’s most vulnerable countries.” Abuse was so rampant, some countries asked international authorities to intervene.
Mass abuse of the opioid tramadol spans continents, from India to Africa to the Middle East, creating international havoc some experts blame on a loophole in narcotics regulation and a miscalculation of the drug’s danger. The man-made opioid was touted as a way to relieve pain with little risk of abuse. Unlike other opioids, tramadol flowed freely around the world, unburdened by international controls that track most dangerous drugs.
Tramadol is available in war zones and impoverished nations because it is largely unregulated. “But it is widely abused for the same exact reason.” Police were finding tramadol pills on terrorists, who trafficked it to fund their networks. And take it to bolster their capacity for violence.
In 2017, law enforcement reported $75 million worth of tramadol from India was confiscated enroute to the Islamic State terrorist group. Authorities seized 600,000 tablets headed for Boko Haram. In boxes disguised with U.N. logos, another 3 million tablets were found in a pickup truck in Niger. The U.N. said tramadol had a direct role in destabilizing the region.
Nevertheless, individual governments including the U.S., Egypt, Ukraine and India realized the drug’s dangers were greater than has been believed previously and worked to rein in on the tramadol trade.
Most of the tramadol pills were coming from Indian pill factories. In the northern Indian state of Punjab, tramadol pills were everywhere. They were sold as legitimate medication in pharmacies, and hawked as illicit counterfeits by street vendors. Authorities seized hundreds of thousands of tablets, banned most pharmacy sales and shut down pill factories. These efforts drove the price for a ten-pack of tramadol pills from 35 cents to $14.
India has twice the global average of illicit opiate consumption. Researchers estimate 4 million Indians use heroin or other opioids, and a quarter of them live in the Punjab, India’s agricultural heartland bordering Pakistan, where some of the most vulnerable are driven to drugs out of desperation.
The Indian government opened a network of treatment centers, fearful that people who had become addicted to tramadol would turn to heroin. Hordes of people rushed in get in, wanting help managing their painful withdrawal. For some of them, tramadol had become as essential as food.
India regulated tramadol in April 2018. Regulators say exports overseas and abuse at home came down. But they acknowledge that the vastness of the pharmaceutical industry and the ingenuity of traffickers makes curtailing abuse and illegal exports all but impossible. Tramadol is still easy to find.
Although Indian regulators knew massive quantities of manufactured tramadol were leading to countless Indians getting addicted, they were shocked to learn that tramadol was ravaging African nations. An officer with the United Nations Office on Drugs and Crime asked people in the western African nation of Mali in 2016 what was their most pressing concern. They said it was tramadol.
A woman said children stumble down the streets, high on tramadol; parents add it to tea to dull the ache of hunger. “Nigerian officials said at a United Nations meeting on tramadol trafficking that the number of people there living with addiction is now far higher than the number with AIDS or HIV.” In other countries tramadol is thought of as a mood enhancer or treatment for depression and post-traumatic stress. Some take it to endure grueling labor, or to improve sexual stamina.
Cameroon scientists thought they’d discovered a natural version of tramadol in tree roots. But it wasn’t so. Farmers bought the pills and fed them to their cattle to ward off the effects of debilitating heat. “Their waste contaminated the soil, and the chemical seeped into the trees.”
Unfortunately, there isn’t an alternative pain medication for tramadol in the 3rd world. Ironically, relief organizations rely on it in war zones and for natural disasters. It’s used extensively not because it is a good medication, but because it’s uncontrolled. Morphine is more effective, but it’s strictly controlled; and countries are fearful of potential for abuse.
We can and should consider changing tramadol to a more restrictive controlled substance level. We also need to see where the U.S. can assist in the “all but impossible” efforts to control and/or curtail the abuse and illicit use of tramadol. The intermixing of terrorism and tramadol is something any nation—including the U.S.—cannot afford to disregard.
For more information, see: “The Double-Edged Sword of Narco-Terrorism,” “Tramadol Is Not a Safe Opioid” and “Global Troubles with Tramadol.”
