November/December 2020

Tramadol and Hip Fracture
By Mark D. Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 13 No. 6 P. 10

Look beyond its reputation before prescribing this widely used medication.

The perception that tramadol is a safer alternative with less dependence risk than other opioids has greatly contributed to its increased use across the world. However, contrary to this belief, tramadol use comes with significant risks that health care providers should consider closely before prescribing to patients. Furthermore, patients who are deemed appropriate for tramadol use should be warned about the growing list of safety concerns associated with its use. Among the issues with tramadol use is a greater risk of hip fractures compared with the risk associated with several other pain medications, according to new reports.

Tramadol Use Overview
In 1995, tramadol (Ultram) was introduced in the United States as a novel analgesic, with its analgesic properties coming from two complementary mechanisms of action. Like other opioids, tramadol acts on mu-opioid receptors, while also having additional activity as a weak inhibitor of the reuptake of norepinephrine and serotonin, like some antidepressant medications. Ultram was initially promoted as being a safer, noncontrolled opioidlike medication with less potential for abuse than opioids. Soon after its approval, however, there were reports of its abuse and diversion. Then, in August 2014, following nearly two decades of tramadol use as a noncontrolled prescription medication, the Drug Enforcement Agency made all products containing tramadol Schedule IV controlled substances.1

Safety Concerns
Today, tramadol is one of the most widely prescribed narcotic-type analgesic medications in the United States, with 36.5 million prescriptions dispensed in 2018 alone.1 Despite its widespread use, the appropriateness of this level of tramadol prescribing is questionable, as safety concerns have been widely reported, including a recent report that tramadol use is linked to greater hip fracture risk than that associated with several other common pain medications, as well as a report that tramadol is used as long as or longer than other widely abused opioids (eg, hydrocodone and oxycodone). These issues are in addition to previously reported tramadol safety concerns including possible withdrawal symptoms, increased emergency department (ED) visits, overdose risk, serotonin syndrome, seizures, and hypoglycemia.

Increased Hip Fracture Risk
Earlier this year, a team of investigators from Boston University School of Medicine, the University of California School of Medicine, and Massachusetts General Hospital sought to evaluate tramadol’s safety profile with regard to hip fracture risk.2 The investigators conducted an analysis of The Health Improvement Network (THIN) database, consisting of medical records for 17 million persons from more than 700 general practice sites across the United Kingdom from 2000 through 2016. The database provided the investigators with access to information including patients' anthropometrics, socio-demographics, lifestyle habits, general practitioner visit details, diagnoses from specialists’ evaluations and hospital admissions, and laboratory testing results.

For their analysis, investigators included patient information for patients aged 50 or older with no history of hip fracture, cancer, or opioid use disorder. The study’s primary outcome measure was incidence of hip fracture during each one-year follow-up period. From the 372,372 patients meeting inclusion criteria, investigators created five propensity score-matched cohorts comparing tramadol use against use of other pain medications including the opioid codeine and the NSAIDs naproxen, ibuprofen, celecoxib, or etoricoxib.

Analyses revealed the risk of hip fracture was higher in those in the tramadol group than those in any of the other medication cohorts. The risk of hip fracture was higher in the tramadol cohort than in naproxen (2.9 per 1,000 person-years for tramadol vs 1.7 per 1,000 person-years for naproxen; HR 1.69, 95% CI, 1.41–2.03), ibuprofen (3.4 per 1,000 person-years for tramadol vs 2 per 1,000 person-years for ibuprofen; HR 1.65, 95% CI, 1.39–1.96), celecoxib (3.4 per 1,000 person-years for tramadol vs 1.8 per 1,000 person-years for celecoxib; HR 1.85, 95% CI, 1.4–2.44), etoricoxib (2.9 per 1,000 person-years for tramadol vs 1.5 per 1,000 person-years for etoricoxib; HR 1.96, 95% CI, 1.34–2.87), and codeine (3.7 per 1,000 person-years for tramadol vs 2.9 per 1,000 person-years for codeine; HR 1.28, 95% CI, 1.13–1.46) cohorts.

In their report of the findings, the study’s investigators suggested the increased risk of hip fracture observed may be related to certain tramadol side effects—including the risk of seizures, dizziness, or delirium—that have been reported in other studies. Furthermore, they indicated that the findings of this study combined with the potential for negative impact on morbidity, higher costs, and overall health associated with hip fracture, suggest that clinical treatment guidelines recommending tramadol use should be reconsidered.

Risk of Prolonged Use
Perceptions that long-term abuse of tramadol is significantly less than that of other opioids are likely unfounded. For example, a 2017 Centers for Disease Control and Prevention report on opioid use found that 13.7% of persons prescribed tramadol had continued use at one year compared with 4.7% to 8.9% for other short-acting opioids (eg, hydrocodone, oxycodone).3

And last year, investigators from a Mayo Clinic study commented that tramadol use may not be the safer, low-risk opioid many consider it to be after finding that patients receiving tramadol for postoperative pain to be at similar or greater risk of prolonged use as those receiving other opioids.4 Using a retrospective analysis of claims data from the OptumLabs Warehouse (commercial insurance and Medicare Advantage patients), the investigators sought to determine the risk to patients who transition from acute to prolonged use of tramadol in opiate-naïve patients treated for postoperative pain using tramadol. For the study, three commonly used definitions of prolonged opioid were used: additional opioid use (defined as at least one opioid fill 90 to 180 days after surgery), persistent opioid use (any span of opioid use starting in the 180 days after surgery and lasting ≥90 days), and CONSORT definition (an opioid use episode starting in the 180 days after surgery that spans ≥90 days and includes either ≥10 opioid fills or ≥120 days’ supply of opioids).

Patients included in the study underwent one of 20 commonly performed surgeries between January 1, 2009, and June 30, 2018. The surgeries were chosen with the aim of including common inpatient and outpatient procedures from multiple specialties and spanning differing degrees of expected postoperative pain. Patients were excluded if they had multiple unrelated procedures on the same day, experienced an inpatient stay longer than seven days, or were admitted as an inpatient more than one day before surgery, and also patients receiving noncancer surgeries if they had cancer. In addition, patients receiving hospice services and those who had a stay in a skilled nursing facility within a day of discharge were also excluded.

524,318 patients met the inclusion requirements, of which 444,764 were followed for at least 180 days and 357,884 had a discharge prescription for one or more opioids. 13,519 (3%) patients received tramadol alone while 5,457 (1.2%) received tramadol along with another short-acting opioid. Women appeared to be more likely to receive tramadol (62.1% of tramadol alone vs 49% of total cohort). Patients discharged with larger prescriptions based on morphine milligram equivalents (MME) were found to have an associated higher risk of prolonged opioid use across all definitions of prolonged use. Receiving 500 MME was associated with nearly five times the risk of prolonged opioid use compared with the receipt of 1 to 199 MME using the CONSORT definition of prolonged use and more than six times the risk of persistent use. Furthermore, receipt of tramadol was also associated with increased adjusted risk across all definitions of prolonged opioid use. Patients receiving tramadol alone had a 6% increased risk of additional opioid use relative to people receiving other short-acting opioids, a 47% increase in the adjusted risk of persistent use, and a 41% increase in the adjusted risk of a CONSORT chronic use episode.

Along with their study findings, the investigators wrote that despite tramadol only being a Schedule IV controlled substance, it has a similar or somewhat greater risk of prolonged opioid use after surgery as do some Schedule II drugs such as hydrocodone and oxycodone. Based on this risk, they suggested that the Drug Enforcement Agency should consider rescheduling tramadol to a level that better reflects its risk for prolonged use.

Withdrawal Symptoms
As with other opioids, withdrawal symptoms may occur if tramadol is discontinued abruptly. Withdrawal symptoms are believed to occur not only due to tramadol’s activity on opioid mu receptors but also as a result of its action as a serotonin and epinephrine reuptake inhibitor. Typical withdrawal symptoms may include gastrointestinal pain, anxiety, bone pain, depression, diarrhea, insomnia, epiphora, nausea, agitation, rhinorrhea, and excessive perspiration. Atypical symptoms are more severe and include severe anxiety; panic attacks; unusual central nervous system (CNS) symptoms such as confusion, delusion, derealization, depersonalization, and paranoid thoughts; and unnatural sensory experiences such as numbness, tingling, prickling, tinnitus, and hallucinations.5 Slowly tapering tramadol doses is recommended to help minimize withdrawal symptoms.

Increased Risk of ED Visits
In 2011, there were an estimated 54,397 ED visits involving tramadol, with 50% or 27,421 being attributed to adverse reactions.6 Tramadol-related ED visits due to adverse reactions increased 150% from 2005 (10,091 visits) to 2011 (27,421). Risk for tramadol ED visits was noted to increase with age. In 2005 to 2011, there was a 389% increase in tramadol-related ED visits in persons aged 45 to 54, while there was a 480% increase in persons aged 55 and older (900 ED visits in 2005 vs more than 5,000 in 2011). Older adults are particularly vulnerable, with patients aged 65 and older accounting for approximately one-third (35%) of tramadol-related ED visits involving adverse reactions, with approximately one-half of these older adults being hospitalized.

Overdoses
Patients taking tramadol should be counseled about the risk of overdose when taking tramadol, especially when taken along with other CNS depressant medications. Tramadol overdosage can cause CNS depression, respiratory depression, and death. Deaths have frequently been reported as either a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. Persons at greatest risk are those who take tramadol in combination with other drugs known to be CNS depressants such as sedatives, tranquilizers, muscle relaxers, antidepressants, opioids, and alcohol.

Seizures
In general, older adults are susceptible to the effects of medications, including drug-induced seizures. Persons aged 65 and older account for nearly 25% of new seizures, with increased risk often due to underlying changes in the brain caused by stroke, heart disease, Alzheimer's disease, and brain tumors.7 Tramadol-related seizures have been reported in patients receiving tramadol within the recommended dosage range and as early as the first dose. Patients who are taking other medications known to reduce seizure threshold (eg, antipsychotics) and patients with a history of seizure or recognized risk of seizure, such as from head trauma, metabolic disorders, alcohol and drug withdrawal, and CNS infections, are at the greatest risk.

Serotonin Syndrome
Serotonin syndrome can occur in individuals taking medications that increase serotonin levels and cause them to accumulate.8,9 Symptoms can range from mild to severe and may be nonspecific, including fast heart rate, high blood pressure, dilated pupils, overreactive reflexes, and/or elevated body temperature. Clinicians are frequently unfamiliar with the condition, with 85% of physicians reported as being unfamiliar with the diagnosis or treatment of serotonin syndrome or the drugs or drug combinations that are potentially involved.9

When patients begin taking tramadol or increase the dose, they should be counseled to watch for symptoms of serotonin syndrome, which can be reversed if detected early. While serotonin syndrome is most frequently caused by use of selective serotonin reuptake inhibitor antidepressants, other drugs can also lead to it, such as opioid analgesics, antibiotics, antimigraine agents, illicit drugs, and over-the-counter drugs alone or in combination. These drugs can interact with tramadol and can increase the risk of serotonin syndrome. Patients taking tramadol should be advised to check with their prescribers or pharmacists before taking new prescriptions, including over-the-counter medications and herbal remedies such as St. John's Wort, nutmeg, or 5-HTP, which are also implicated in possible serotonin syndrome.

Prothrombin Time/International Normalized Ratio Prolongation With Warfarin
Prolongation of the international normalized ratio (INR) and prothrombin time and extensive ecchymosis have been reported in patients receiving both tramadol and warfarin. INR may be increased up to three-fold.10 Recommend checking INR three days after patients start or increase/decrease doses of tramadol. Advise patients to watch for signs of bleeding.

Hypoglycemia
Patients taking tramadol are also at an increased risk for hypoglycemia. From a 2013 study, patients taking tramadol who experienced hypoglycemia were found to have an average blood glucose level of 45 mg/dL.11 Although most patients experienced mild to moderate signs of hypoglycemia, approximately 30% experienced severe neurological symptoms such as coma or convulsions. Most cases of hypoglycemia occurred within 10 days of starting tramadol therapy, with the median occurrence at five days. Patients at greatest risk where elderly patients with at least one risk factor such as diabetes or renal insufficiency.

In a second study, published in 2015, researchers conducted a retrospective analysis of 334,034 patients (28,110 new users of tramadol and 305,924 new users of codeine) of whom 1,105 were hospitalized for hypoglycemia, with 112 patients dying as a result of hypoglycemia.12 Compared with codeine use, tramadol use was associated with a 52% increased risk of hospitalization. Patients appear to be at the greatest risk of hospitalization due to hypoglycemia during the first 30 days of initiating tramadol. Results of the analysis showed a greater than three-fold increase in hospitalization for hypoglycemia in those patients who had started taking tramadol within the prior 30 days.

Final Thoughts
While the use of tramadol may be appropriate for some patients, caution is warranted, as safety concerns are real. Prescribers are encouraged to start with low doses and to increase slowly when necessary. As with other opioids, patients should be provided only a few days’ supply of tramadol and clinicians should discuss with patients concerns regarding dependence issues, overdose risk, drug-interaction risks including possible serotonin sydrome and other possible adverse drug effects.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
1. Drug Enforcement Administration. Tramadol (trade names: Ultram, Ultracet). https://www.deadiversion.usdoj.gov/drug_chem_info/tramadol.pdf. Published March 2020.

2. Wei J, Lane NE, Bolster MB, et al. Association of tramadol use with risk of hip fracture. J Bone Miner Res. 2020;35(4):631-640.

3. Shah A, Hayes CJ, Martin BC. Characteristics of initial prescription episodes and likelihood of long-term opioid use - United States, 2006-2015. MMWR Morb Mortal Wkly Rep. 2017;66(10):265-269.

4. Thiels CA, Habermann EB, Hooten WM, Jeffery MM. Chronic use of tramadol after acute pain episode: cohort study. BMJ. 2019;365:l1849.

5. Rajabizadeh G, Kheradmand A, Nasirian M. Psychosis following tramadol withdrawal. Addict Health. 2009;1(1):58-61.

6. Bush DM. Emergency department visits for adverse reactions involving the pain medication tramadol. Substance Abuse and Mental Health Services Administration website. http://www.samhsa.gov/data/sites/default/files/report_1965/ShortReport-1965.html. Published May 14, 2015.

7. Ramsay RE, Rowan AJ, Pryor FM. Special considerations in treating the elderly patient with epilepsy. Neurology. 2004;62(5 Suppl 2):S24-S29.

8. Mackay FJ, Dunn NR, Mann RD. Antidepressants and the serotonin syndrome in general practice. Br J Gen Pract. 1999;49(448):871-874.

9. Iqbal MM, Basil MJ, Kaplan J, Iqbal MT. Overview of serotonin syndrome. Ann Clin Psychiatry. 2012;24(4):310-318.

10. Baxter K. Stockley's Drug Interactions [online]. Medicines Complete website. https://about.medicinescomplete.com/#/browse/stockley. London: Pharmaceutical Press.

11. Bourne C, Gouraud A, Daveluy A, et al. Tramadol and hypoglycaemia: comparison with other step 2 analgesic drugs. Br J Clin Pharmacol. 2013;75(4):1063-1067.

12. Fournier JP, Azoulay L, Yin H, Montastruc JL, Suissa S. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med. 2015;175(2):186-193.