Use of Tramadol for Arthritis Linked to Increased Risk of Death

Accounting for approximately 41 million prescriptions dispensed in the U.S. in 2017,[1] the opioid analgesic tramadol (CONZIP, ULTRAM) is among the most widely used painkillers. Additionally, clinical practice guidelines advocate its use as the first-line treatment of chronic pain, including pain related to osteoarthritis.[2],[3]

Public Citizen’s Health Research Group has designated tramadol as Do Not Use since 1999.[4] Even in the first few years after its approval by the Food and Drug Administration in 1995, tramadol did not appear to be as effective as other painkillers and was linked to serious adverse events, including seizures and dependence.

A new study published in the March 12, 2019, issue of the Journal of the American Medical Association (JAMA) found that tramadol use was associated with a higher risk of death than use of several commonly used nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with osteoarthritis, the most common form of arthritis.[5] These findings reinforce our Do Not Use designation for tramadol.

About tramadol

Tramadol is a synthetic opioid. It is approved for use in adults with pain severe enough to require an opioid analgesic for which alternative treatments are inadequate.[6] It also is available in combination with acetaminophen (ULTRACET).[7]

Tramadol’s analgesic effect has been characterized as weak. For example, a review of multiple studies of tramadol use in patients with osteoarthritis found that it had only small benefits when taken for up to three months.[8] The review also noted that the drug’s adverse effects led many patients to stop taking it, limiting its usefulness.

Despite the impression among many clinicians that tramadol is safer than other opioids, there have been reports of increasing numbers of deaths linked to the drug. For example, data on drug poisonings from England and Wales showed that the number of deaths related to this drug nearly tripled from 2009 to 2014.[9],[10]

Tramadol also comes with a worrisome list of serious adverse effects, including seizures (even when taken at the recommended dosage), addiction, dangerous interactions with other drugs, impaired breathing and death.[11] One particularly dangerous but rare adverse effect for tramadol is serotonin syndrome, a life-threatening condition characterized by agitation, hallucinations, coma, rapid heartbeat, rapid changes in blood pressure, increased body temperature, nausea, vomiting, diarrhea and muscle rigidity.

Importantly, the FDA-approved tramadol label has been modified over the years to include new information regarding tolerance (the need for increasing doses to maintain its analgesic effect) and abuse. Withdrawal symptoms, such as anxiety, nausea, sweating and tremors, may occur if tramadol is discontinued abruptly.

The new JAMA study[12]

Using an electronic medical records database derived from the records of 580 general practices in the U.K. for approximately 11 million patients, researchers from the U.S. and China identified patients age 50 or older who had been diagnosed with osteoarthritis and visited a general practitioner between 2000 and 2015.

The researchers then compared the rate of death from any cause over a one-year period between osteoarthritis patients who received an initial prescription for tramadol and patients who received an initial prescription for one of the following five medications: the nonselective NSAIDs naproxen (ALEVE, ANAPROX DS, NAPRELAN, NAPROSYN) or diclofenac (CAMBIA, ZIPSOR, ZORVOLEX), the selective COX-2 inhibitor NSAIDs celecoxib (CELEBREX) or etoricoxib (not marketed in the U.S.), or the weak opioid codeine (generic only).

To minimize the chances of bias, for each comparison, the researchers matched a group of patients prescribed tramadol with a similar group prescribed one of the other five drugs based on a variety of demographic, social, lifestyle and medical factors — including age, sex, body size, drinking habits, smoking status, duration of osteoarthritis, and other medical conditions.

The total number of osteoarthritis patients included in the study was approximately 89,000. The patients had a mean age of 70 and 61% were women. Unsurprisingly, the proportion of patients who were prescribed tramadol increased from 3% in 2000 to 11% in 2013 and 10% in 2015.

The researchers found that after 12 months of follow-up, there was an approximately twofold greater risk of death from any cause for patients who were prescribed tramadol than patients prescribed any of the four NSAIDs. This difference was statistically significant in all four cases. In contrast, there was no difference in rate of death between patients prescribed tramadol and those prescribed codeine. The researchers noted that because of limitations in their study design, further research will be needed to determine if tramadol causes an increased risk of death in osteoarthritis patients.

What You Can Do

You should avoid taking tramadol if you are not currently taking it. If you are currently using tramadol, you should talk to your doctor about gradually tapering off the drug — because it is addictive — and switching to a non-opioid pain reliever, such as naproxen or acetaminophen (TYLENOL), or trying nonpharmaceutical treatments. Note that we have designated oral diclofenac and celecoxib as Do Not Use. Nondrug approaches to pain management — such as physical therapy, meditation, exercise and weight loss — may be harder to implement than painkiller medications, but they are safe and effective for many patients.
 

References

[1] Drug Enforcement Administration. Tramadol (trade names: Ultram, Ultracet). October 2018. https://www.deadiversion.usdoj.gov/drug_chem_info/tramadol.pdf. Accessed June 4, 2019.

[2] Jevsevar DS. Treatment of osteoarthritis of the knee: Evidence-based guideline, 2nd edition. J Am Acad Orthop Surg. 2013;21(9):571-576.

[3] Hochberg MC, Altman RD, April KT, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken). 2012;64(4):465-474.

[4] Painkiller tramadol increases risk of low blood sugar. Worst Pills, Best Pills News. May 2015. /newsletters/view/962. Accessed June 4, 2019.

[5] Zeng C, Dubreuil M, LaRochelle MR, et al. Association of tramadol with all-cause mortality among patients with osteoarthritis. JAMA. 2019;321(10):969-982.

[6] Janssen Pharmaceutical Companies. Label: tramadol (ULTRAM). April 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020281s041lbl.pdf. Accessed June 4, 2019.

[7] Janssen Pharmaceuticals. Label: tramadol and acetaminophen (ULTRACET). September 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021123s016s017lbl.pdf. Accessed June 4, 2019.

[8] Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis: A systematic review and metaanalysis. J Rheumatol. 2007;34(3):543-555.

[9] Office for National Statistics. Deaths related to drug poisoning in England and Wales: 2013. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/bulletins/deathsrelatedtodrugpoisoninginenglandandwales/2014-09-03. Accessed June 4, 2019.

[10] Office of National Statistics. Deaths related to drug poisoning in England and Wales: 2014 registrations. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/deaths/bulletins/deathsrelatedtodrugpoisoninginenglandandwales/2015-09-03. Accessed June 4, 2019.

[11] Janssen Pharmaceutical Companies. Label: tramadol (ULTRAM). April 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020281s041lbl.pdf. Accessed June 4, 2019.

[12] Zeng C, Dubreuil M, LaRochelle MR, et al. Association of tramadol with all-cause mortality among patients with osteoarthritis. JAMA. 2019;321(10):969-982.