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Tramadol: The “Safe” Opioid?
Imagine a safe and non-addictive pain medicine that is as good as morphine for mild to moderate pain. Sounds too good to be true, right?1
This is how tramadol is marketed and perceived—as a better opioid due to its excellent pain-relieving qualities coupled with a reduced risk of respiratory depression and low addictive potential. On paper, this sounds wonderful and should be a staple in any podiatrist’s post-operative pain course. However, digging deeper into the pharmacology of tramadol reveals something far more concerning.
The current opioid epidemic in the United States results in over 75,000 deaths per year.2 This issue stems from both the regular use (and abuse) of prescription drugs which may lead towards illicit alternatives, such as heroin and fentanyl. These opiate compounds are remarkably addictive and have the potential to be incredibly dangerous as demonstrated by the fact that 80% of modern heroin users report prescription opioid abuse prior to using heroin.3,4 A harrowing figure from Manchikanti et al demonstrates that 99% of the world’s hydrocodone and 80% of the oxycodone is being used in America, despite the fact that America only holds 4.6% of the world’s population.5
What You Should Know About Tramadol’s Mechanism of Action
The mechanism of action of tramadol is what makes its use uncertain. It has both monoaminergic reuptake inhibitory and opioid receptor agonist activity, but it is metabolized in unknown amounts. Tramadol is a prodrug and the parent compound is very similar to the common serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine (Effexor XR, Viatris), with extremely weak mu agonism. This produces analgesia by affecting the central modulation of pain as well as the nociceptive process.
The majority of the opioid effects come from the metabolite M1 (O-desmethyltramadol), which is metabolized by the cytochrome P450 enzyme CYP2D6. However, there is a substantial amount of variability in CYP2D6 isozymes among different populations.6,7 Patients can metabolize the SNRI compound to the opioid either very quickly or very slowly—a factor you would not discover unless the patient submits to genetic testing. If the patient is a poor metabolizer (common in African Americans, Caucasians, and some Asians), they may only get 3% of the intended dose of an opioid, and significantly more of the monoaminergic reuptake inhibitor. Conversely, if patients are on the opposite end of the spectrum (such as Egyptians, Iranians, and Saudi Arabians) with potentially multiple copies of the CYP2D6 gene, 86% can be metabolized to the opioid, leading to very high levels of abuse of tramadol among these populations.8
When prescribing tramadol, the physician is essentially giving an unknown ratio of an SNRI and an opioid, which may be problematic if your primary goal is pain control. The ratio and true dose given is heavily dependent on the patient’s CYP2D6 genotype as well as other drug–drug interactions. In these cases, patients may experience excessive serotonin effects with concurrent underalgesia, or excessive opioid effects, leading to abuse potential, withdrawal, dependence, and the complications that go along with those. You won’t know what your patient will experience when taking tramadol, so why risk it?
Additionally, if your patient is simultaneously consuming selective serotonin reuptake inhibitors (SSRIs), which strongly inhibit CYP2D6, this predictably leads to an under-metabolization of the tramadol parent compound, leading to an increase in serotonergic activity and decrease in opioid, or pain-relieving activity. Tramadol can also cause significant hypoglycemia in patients suffering from both type 1 and type 2 diabetes mellitus due to the serotonergic effects in the central nervous system (CNS) inhibit the counter-regulatory hormonal response and tramadol activates peripheral GLUT4 receptors.
When Tramadol Can Negatively Affect Patients
There have been multiple trials demonstrating hypoglycemia in these patients with diabetes and in one specific case-control study: 46.8% of patients with type 1 diabetes and 16.8% of patients with type 2 diabetes suffered from hypoglycemia after administration of tramadol.9,10 Even at subtherapeutic doses tramadol lowers the seizure threshold of patients and even those without a history of epilepsy may be more likely to seize.11 It produces seizures through inhibitory effects on GABA receptors, nitric oxide, and serotonin reuptake, as well as by increasing lipid peroxidation and free radicals, which all lead to neurotoxicity. Further, abrupt cessation of tramadol increases the risks for SNRI and opioid withdrawal syndromes.
Tramadol can also be toxic in patients who have existing comorbidities, which can be common in the patient population undergoing foot and ankle surgery. In patients who have renal failure, there is a two-fold increase in the half-life of tramadol and the M1 metabolite, which could induce respiratory depression or precipitate a seizure.12 For patients who have liver failure, there is also potential toxicity due to the CYP2D6, which becomes very easily saturated, also leading to the aforementioned untoward reactions.13 In those patients who are taking SSRIs, not only is there increased serotonin, but SSRIs also inhibit CYP2D6, which further increases the parent compound and there can be an inadvertent induction of serotonin syndrome, which is potentially fatal.14
Long-term use of tramadol is also associated with Alzheimer’s and Parkinson’s diseases, as well as seizures and serotonin syndrome (independent of other medications). The association with Alzheimer’s is similar to the native disease process and due to the decreased concentration of intracellular signaling molecules, like cGMP, cAMP, and PKC, which affect both learning and memory. Inhibition of the GABA-A receptors also interferes with dopamine synthesis. The effect on these receptors is responsible for motor symptoms and this reduced dopamine can cause bradykinesia and tremors, which are the primary motor symptoms in Parkinson’s.15
Lastly, in a post-operative pain setting, giving ondansetron and tramadol reduces the efficacy of both, as the former is a serotonin antagonist while the latter partially depends on enhanced serotonergic transmission for efficacy.16
Is Tramadol That Effective for Musculoskeletal Pain?
The effectiveness of tramadol for musculoskeletal pain has also recently come under fire. Several recent studies by Zeng and other authors demonstrated that in patients who were suffering from osteoarthritis, tramadol may be associated with all-cause mortality, hip fractures, and myocardial infarctions compared to non-steroidal anti-inflammatory drugs (NSAIDs).17–19 This was likely due to respiratory depression, hypoglycemia, or postoperative delirium. There needs to be more research to determine if the association is causal. However, without a significant increase in pain control, there seems to be no benefit over NSAID therapy.17-19
One study established that 75mg of tramadol and 650mg of acetaminophen was no more effective at pain control than 400mg of ibuprofen.20 Edwards et al reviewed five randomized controlled trials and found that for post-operative pain, tramadol and acetaminophen was similarly effective to 400mg of ibuprofen.21 Specifically in the foot and ankle, Brattwall et al found that etoricoxib (Arcoxia, Merck) was more effective at analgesia than tramadol after hallux valgus surgery.22
There may be some concern about using high doses of anti-inflammatories after osseous surgery. However, there is no high-quality clinical data to support the theory that it suppresses bone healing in any way.23-25 A recent meta-analysis in oral surgery patients found that alternating 400mg ibuprofen and 1000mg acetaminophen every 4 hours provided almost complete pain relief.26 To augment the ibuprofen and acetaminophen, one could also prescribe a few tablets of oral morphine for breakthrough pain. Oral morphine is one of the opioids with the least addictive potential and fewer euphoric effects, and unlike tramadol, when oral morphine is given, you are not rolling the proverbial dice on the amount of pain control you get.27
In Conclusion
Treating postoperative pain for many foot and ankle surgeries should not be anchored with copious amounts of opioids. The concept of postoperative pain is an especially complex topic that has many psychological components.
A particularly interesting study compared pain medication after ankle surgery in Dutch and American patients.28 Researchers found that after identical procedures, American patients used significantly more opioids and pain medicine in general. This is probably due to the state of mind of postoperative patients, and the expectation of American patients to be in absolutely no pain after surgery.
However, during the majority of foot and ankle surgery, not only is there soft tissue dissection, but osteotomies, and potentially tendons or ligaments that are cut as well. This is traumatic to the patient, and of course, there will be pain associated with surgical dissection and resulting inflammation. On the other hand, if patients’ expectations are managed preoperatively, and they understand there may be some mild discomfort after the procedure that can be managed very well with compliance, elevation, icing, and regular use of non-opioid pain medicine, it could significantly lessen opioid prescriptions in the United States, even more so than the current downward trend.
Tramadol may offer consistent and appropriate analgesia for some patients who possess the correct genes, but even then, there are many potential side effects to be wary of. Multimodal pain control is important and is part of what makes tramadol so appealing, but it may be prudent to offer medication where the effects are more consistent among populations.
By prescribing tramadol without a good understanding of the patients’ comorbidities, other medications, and their specific genes relating to CYP2D6, you are prescribing a potentially dangerous drug cocktail in unknown ratios, which will have undetermined effects on the patient. When giving postoperative analgesics, if you choose to give an opioid, give one with predictable results where adjunctive therapies can be added on as necessary.
Dr. Ehler is a third-year resident at Highlands-Presbyterian/St. Luke's Residency Program in Denver, CO.
Dr. Kruse is an attending physician and director of research at the Highlands-Presbyterian/St. Luke's Residency Program in Denver, CO.
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