A medication once thought to be the safe alternative to more potent pain medications continues to present problems for its users, especially seniors. In 2019, a study was released from University Hospitals that found Tramadol, the generic version of the drug Ultram being the generic version of the drug, had the ability to interact with common antidepressants, not only making it less effective for pain but also increased the likelihood that users could become addicted since it took upwards of three times more of this medication to control breakthrough pain.
Tramadol, introduced in 1995, was initially marketed as a safer alternative to more powerful narcotics. The method of research included a review of 152 patients who received care at the University Hospitals and were on Tramadol for at least 24 hours. And according to Derek Frost, a pharmacist at University Hospital and the study’s lead author, “As we looked at the secondary analysis, it ended up being four times as much over their entire hospital stay.”
The anti-depressants affected by Tramadol are Prozac (fluoxetine), Paxil (paroxetine), and Wellbutrin (bupropion). Other anti-depressant medications such as Zoloft, Celexa and Lexapro did not appear to inhibit the pain blocking effects of Tramadol.
The History of Tramadol
Let’s look at the history of this drug. Tramadol was first introduced in the United States in 1995 under the brand name Ultram and was initially marketed as a safer non-controlled analgesic with less potential for abuse than traditional opioids. Tramadol quickly became the second most prescribed narcotic-type analgesic, ranking behind only hydrocodone with acetaminophen products.
"Tramadol fits into a group of drugs called opiate agonists...chemically similar to morphine but only about one-tenth as potent."
Tramadol fits into a group of drugs called opiate agonists and was prescribed to treat moderate to severe pain by changing the way the body sensed pain by binding with its opiate receptors. Although chemically similar to morphine, it provided relief but was only about one tenth as potent. Physicians embraced the marketing strategy that Tramadol was much safer than the traditional narcotic pain relievers. Even so, it was not without risks.
Narcotics versus Opioids
Let’s take a moment here to discuss the difference between narcotics and opioids, something many readers of our blog have asked about. The difference is subtle and usually comes down to a legal definition. A narcotic is sometimes mistakenly used to refer to illicit drugs such as heroin (used for a "high"), but legally and medically, a narcotic is any drug that relieves pain. But narcotics are essentially the same thing as opiates and opioids.
Narcotics are any drug that relieves pain, opiates are narcotics that are naturally obtained, opioids are narcotics that are derived synthetically. Drugs like hydrocodone and oxycodone can be described as prescription narcotics, or opioids. Heroin is also considered a narcotic because it acts on the same receptors in the brain and causes the same effects as prescription opioids. Narcotics, opiates, and opioids are all drugs that reduce the intensity of pain signals reaching the brain. They all affect certain areas of the brain that control emotion, which is how they’re able to reduce pain sensations. Again, the only difference between opiates and opioids is that opiates are naturally derived, while opioids are man-made.
Tramadol Dangers Began to Emerge
By 2002, the patent on Ultram expired and the Food and Drug Administration (FDA) approved a generic version of Ultram, called Tramadol, which is now manufactured by multiple drug companies. It was after this when the drug became less expensive and prescribed at higher rates that the problems began to surface.
"By 2011...Tramadol was linked to over 20,000 emergency room visits. In Florida alone, where a high number of elderly individuals were taking this medication, there were 380 overdose deaths."
In 2010, the FDA received information from a study that Tramadol was not to be prescribed for those individuals who exhibited suicidal behaviors, had addiction histories, or were depressed or emotionally disturbed. By 2011, reports were pouring into researchers that Tramadol was linked to over 20,000 emergency room visits around the country. In Florida alone, where a high number of elderly individuals were taking this medication, there were 380 overdose deaths reported.
As reports like this continued to rise, it was apparent that changes needed to be made regarding the prescribing of Tramadol. In 2014, the Drug Enforcement Administration (DEA), stepped in and classified Tramadol as a controlled substance and thus subject to much stricter controls.
As a licensed addictions clinician and clinical trainer in the Commonwealth of Massachusetts for over 30 years before my retirement, I had my own experiences with physicians who were quite liberal in prescribing the drug to older adults despite lengthy histories of drug addiction before it was reclassified as a controlled substance.
Physicians would nearly always assure me that my concerns about Tramadol were “not valid”, stating that it was “not a narcotic” with the implication that it carried no major abuse potential. In fact, many considered this medication to be as safe as over the counter pain relievers like acetaminophen and ibuprofen.
The Opioid Epidemic
This belief made Tramadol a particularly dangerous drug — because it was, as later discovered, a highly addictive substance that was prone to abuse. Those in treatment for addiction would make one phone call and a script for the drug arrived with multiple refills. But because other more powerful opiates and opioids were available on the street for a price not that much different than Tramadol, users opted for the more powerful substance. But then things began to change.
As the so-called opioid epidemic began to hit mainstream media followed by the crackdown on the number of prescriptions being written for pain medications, the Tramadol issue started becoming known.
"At one point, one-third of ER visits for Tramadol involved those over 65."
Those we saw in out-patient were referred to us because they were taken off oxycodone or hydrocodone and put on Tramadol due to the scrutiny providers were receiving around the prescribing of the more powerful narcotics. Many of them suffered from severe arthritis, spinal stenosis or other painful conditions and Tramadol just did not work. So, they took more than the prescribed amount seeking pain relief, unfortunately they developed a tolerance to the medication and developed severe withdrawal symptoms. This change also affected older adults.
At one point, one-third of ER visits for Tramadol issues involved those over age 65. As we discussed in previous blogs, seniors are more susceptible to adverse effects of medications due primarily to an aging body and it is essential for medical providers to recognize that there is a Tramadol associated risk with this group. And Tramadol presents with another problem, which can be deadly, that we will discuss.
Tramadol and CNS Depression
In seniors, Tramadol can cause central nervous system (CNS) depression leading to breathing problems and death. The causes of this CNS depression appear to be the result of using more Tramadol than prescribed to address out of control pain or because of interactions with other medications. Seniors who have been prescribed other medications that depress the CNS like sedatives, tranquilizers, muscle relaxants, antidepressants should be evaluated thoroughly before adding Tramadol to their medication list.
Tramadol has also been associated with seizures in seniors over the age of 65 with nearly 25% of new seizure activity in this group being attributed to the use of this medication. Research seems to indicate that this increase is the result of changes in the brain caused by stroke, heart disease, Alzheimer's disease, and brain tumors.
In seniors with existing renal disease or diabetes, according to one study, Tramadol has been associated with hypoglycemia, although in a small number of cases those without the risk factors also developed hypoglycemia. Compared with codeine, Tramadol use was associated with a 52% increased risk of hospitalization and appeared to be at the greatest risk of hospitalization due to hypoglycemia during the first 30 days of initiating Tramadol use.
Tramadol and Serotonin Syndrome
We know Tramadol’s action on the opiate receptors of the body, but it also has an incredibly unique feature that can also contribute to dependence in its users. This drug exerts some of its effects through actions on serotonergic and noradrenergic neurotransmission, which increases brain levels of the neurotransmitters serotonin and norepinephrine. These changes are similar to those induced by antidepressant drugs like venlafaxine (Effexor).
What does this mean? Not only does Tramadol affect pain levels through its narcotic action, but it also acts as a mood elevator, affecting the pleasure centers of the brain. Yes, addiction is a major concern but there is also another -- its effects on serotonin can lead to a potentially deadly condition called serotonin syndrome.
Serotonin is a chemical produced by our body that allows brain cells and other nervous system cells to communicate with one another. When there is too little serotonin in the brain, depression is the result. But too much serotonin can lead to excessive nerve cell activity, causing a potentially deadly collection of symptoms known as serotonin syndrome, which can be potentially lethal.
According to the Mayo Clinic, symptoms often begin within hours of taking any new medication that affects serotonin levels or excessively increasing the dose of one that is being used. These symptoms include, confusion, agitation or restlessness, dilated pupils, severe headache, changes in blood pressure and/or temperature, nausea and/or vomiting, diarrhea, rapid heart rate, tremor, loss of muscle coordination or twitching muscles and irregular heartbeat. What is concerning is that in seniors, several of these symptoms are already present due to preexisting conditions, so attention needs to be paid when starting a senior on Tramadol or increasing the dosage.
The drugs most associated with serotonin syndrome and Tramadol use are the selective serotonin reuptake inhibitors (SSRIs), a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder and anxiety disorders. Some of the most prescribed SSRIs are:
Complicating matters even further is the fact that according to multiple reputable medical researchers, more than 85% of physicians are unfamiliar with the diagnosis or treatment of serotonin syndrome or the drugs or drug combinations that are potentially involved. Although they say that providers are more apt to spot serotonin syndrome in younger patients, it is exceedingly difficult to diagnose in seniors as many of the symptom's mimic conditions already present. The key would be having knowledge that a new medication is being used and what other drugs interact with Tramadol that could lead to this condition. Drugs that are cause for concern when used with Tramadol are:
Blood thinners such as Warfarin
Antifungals, including ketoconazole (Nizoral)
Antibiotics such as erythromycin, linezolid and rifampin
Psychotropics used to treat schizophrenia and bi-polar disorder, this includes lithium-based medications
Other medications for psychiatric issues besides SSRIs. These include monoamine oxidase inhibitors (MAO), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants like amitriptyline.
Heart medications which include digoxin and Quinidine
Other narcotic pain medications
Medication for migraine headaches which include almotriptan (Axert), eletriptan (Relpax) and frovatritan (Erova)
Medications for seizures which include carbamazepine (Equetro and Tegretol)
Muscle relaxers like Flexeril
Even over the counter supplements like St. John’s Wort (which can increase serotonin levels)
Education and Counseling
So, what needs to be done? Counseling older adults using Tramadol is imperative to prevent future issues. Seniors prescribed Tramadol, as well as their families or caretakers, need to be counseled to watch for symptoms of serotonin syndrome, which can be reversed if detected early. With the ongoing concerns about prescribing some of the stronger opiates and seniors experiencing the painful conditions associated with aging, it is a good bet that Tramadol will continue to be prescribed at high rates. Given that, education is the key.
“With the trend towards keeping seniors in their homes and out of institutional care, it is imperative that family members and home health care providers have knowledge of the medications their loved ones or clients are prescribed, thoroughly understanding why they are using them and what side-effects or drug interactions are possible,” said Attorney Connelly.
"Further, all medications should be counted on a regular basis to ensure that they are being taken as directed," Attorney Connelly continued. "Staying in the home without the constant oversight of medical professionals means that those with day-to-day contact with the senior are the first line of defense in keeping them safe and medication compliant."
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