Painkiller Tramadol Increases Risk of Low Blood Sugar

Accounting for approximately 44 million prescriptions in the U.S. in 2013,[1] tramadol (ULTRAM) has become a widely used analgesic (painkiller). Additionally, clinical guidelines increasingly advocate its use for the treatment of chronic pain.[2]

The popularity of tramadol since its approval by the Food and Drug Administration (FDA) in 1995[3] is most likely due to aggressive marketing of the drug to clinicians. The drug is touted as an effective and safe medication,[4] but in truth, it is far from that.

Public Citizen’s Health Research Group has designated tramadol as Do Not Use since 1999. Even in the first few years after its approval, tramadol did not appear to be as effective as other painkillers and was linked to serious adverse events, including seizures and dependence.[5]

A new study published in the Feb. 1 issue of JAMA Internal Medicine brings to light evidence regarding another, unanticipated adverse effect for tramadol: hypoglycemia (low blood sugar).[6]

About tramadol

Tramadol is a synthetic painkiller that belongs to a class of drugs known as opiate agonists.[7] It is approved for the treatment of moderate to moderately severe pain in adults.[8] It also is available in combination with acetaminophen (ULTRACET).[9]

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 small benefits when taken for up to three months. The review also noted that the drug’s adverse events led some to stop taking it, limiting its usefulness.[10]

Also concerning is the unpredictable way tramadol is broken down in the body, which can affect the drug’s safety and effectiveness. Approximately 7 percent of white patients metabolize the drug slowly and therefore may experience greater analgesic effect and adverse side effects.[11] In contrast, nearly 10 percent of Italians, Portuguese and Greeks, as well as roughly one-third of East Africans and people from the Arabian Peninsula, metabolize the drug quickly and thus may need higher doses to achieve the same degree of pain relief.[12] Despite the impression among many clinicians that tramadol is safer than other opioids, there have been increased reports of death involving this drug: Data from England and Wales show that the number of deaths related to this drug almost tripled from 2009 to 2013.[13]

Tramadol also comes with a worrisome list of warnings, including severe allergic reactions,[14] seizures, addiction, interactions with other drugs, slowed breathing and death.

One particularly dangerous adverse event for tramadol is serotonin syndrome, a life-threatening condition characterized by agitation, hallucinations, coma, rapid heartbeat, rapid changes in blood pressure, increased body temperature and other symptoms.

Importantly, the FDA-approved tramadol label has been modified over the years to include new information regarding diminished response to the drug, the need for increasing doses to maintain its effect and abuse. Withdrawal symptoms — anxiety, nausea, tremors and upper respiratory issues — may occur if tramadol is discontinued abruptly.

Tramadol was classified as a controlled substance by the Drug Enforcement Administration because it has many chemical similarities to narcotic drugs such as morphine and codeine.[15] This new classification imposed additional recordkeeping, office visit and drug-testing requirements for this potentially addictive drug.

Study shows link to hypoglycemia

The new study is the first analysis of population-based data — collected from hospital and office visits of ordinary patients who were not part of an experimental study — that examined the link between tramadol use and hypoglycemia, compared with the painkiller codeine. The study, conducted by Canadian and French researchers, used large databases that included information on prescription drugs, medical diagnoses and hospitalizations from April 1, 1998, to March 1, 2012.

The researchers compared the rate of hospitalizations for hypoglycemia-related events among 334,000 adults who were prescribed either tramadol or codeine for noncancer pain.

The researchers followed patients for an average of five years and found that just over 1,100 patients were hospitalized for hypoglycemia among users of either drug. Overall, tramadol use was associated with a 50 percent greater risk of hospitalization for hypoglycemia, compared with similar patients who received codeine. This increased risk was most pronounced during the first 30 days of tramadol use, when it was about three times higher compared with codeine users. The hypoglycemia cases identified in the study sometimes proved fatal — more than 110 patients died from this condition.

The true rate of tramadol-induced hypoglycemia is likely to be higher than that reported in the study because hypoglycemia may not be reported in diabetics and may not even be recognized in patients without diabetes. Moreover, most cases of hypoglycemia do not result in a hospital admission — which is the only outcome examined in the study.[16]

Because the study was not a randomized experiment, it is hard to establish a definitive cause-and-effect relationship between tramadol use and the development of hypoglycemia. However, it was much larger and better designed than prior non-experimental studies that suggested a link between hypoglycemia and tramadol use.[17] One such study analyzing adverse-event reports filed by patients in France identified 43 tramadol-related hypoglycemia cases between 1997 and 2010.[18] Most of these events also occurred soon after initiation of tramadol therapy (77 percent within just 10 days of starting treatment). Cases were more frequent in the elderly and those with diabetes, although 60 percent of patients who developed hypoglycemia did not have diabetes.

What You Can Do

If you are currently using tramadol or tramadol and acetaminophen to relieve chronic noncancer pain, you should talk with your health care provider about gradually tapering off the tramadol — because it is addictive — and switching to non-opioid pain relievers or trying nonpharmaceutical treatments. In particular, consult with your health care provider to identify the root cause for your chronic pain. Often, chronic noncancer pain is caused by an injury or inflammation — therefore, it would be ideal to treat the underlying cause rather than just the pain. Specifically, 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 in many patients.

References

[1] Drug Enforcement Administration, Office of Diversion Control. Tramadol. July 2014. http://www.deadiversion.usdoj.gov/drug_chem_info/tramadol.pdf. Accessed March 18, 2015.

[2] Nelson LS, Juurlink DN. Tramadol and hypoglycemia — one more thing to worry about. JAMA Intern Med. 2015;175(2):194-195. doi:10.1001/jamainternmed.2014.5260.Conflict.

[3] Drug Enforcement Administration, Office of Diversion Control. Tramadol. July 2014. http://www.deadiversion.usdoj.gov/drug_chem_info/tramadol.pdf. Accessed March 18, 2015.

[4] Nelson LS, Juurlink DN. Tramadol and hypoglycemia — one more thing to worry about. JAMA Intern Med. 2015;175(2):194-195. doi:10.1001/jamainternmed.2014.5260.Conflict.

[5] Do not use! The pain drug tramadol (ULTRAM/ULTRACET) and serotonin syndrome. Worst Pills, Best Pills News. March 2002. /newsletters/view/68. Accessed March 18, 2015.

[6] Fournier J-P, Azoulay L, Yin H, et al. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med. 2015;175(2):186-193. doi:10.1001/jamainternmed.2014.6512.

[7] U.S. Food and Drug Administration. ULTRAM® (tramadol hydrochloride) Tablets Full Prescribing Information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020281s032s033lbl.pdf. Accessed February 24, 2015.

[8] U.S. National Library of Medicine. DailyMed Drug Label: ULTRAM - tramadol hydrochloride tablet, coated . Updated July 2014. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=45f59e6f-1794-40a4-8f8b-3a9415924468. Accessed March 18, 2015.

[9] Drug profile: Tramadol (ULTRAM); tramadol and acetaminophen (ULTRACET). WorstPills.org. /monographs/view/135. Accessed February 24, 2015.

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

[11] Food and Drug Administration. ULTRAM® (tramadol hydrochloride) tablets full prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020281s032s033lbl.pdf. Accessed February 24, 2015.

[12] Nelson LS, Juurlink DN. Tramadol and hypoglycemia — one more thing to worry about. JAMA Intern Med. 2015;175(2):194-195. doi:10.1001/jamainternmed.2014.5260.Conflict.

[13] Office for National Statistics. Deaths related to drug poisoning in England and Wales, 2013. http://www.ons.gov.uk/ons/rel/subnational-health3/deaths-related-to-drug-poisoning/england-and-wales---2013/stb---deaths-related-to-drug-poisoning-in-england-and-wales--2013.html. Accessed February 25, 2015.

[14] U.S. National Library of Medicine. DailyMed Drug Label: ULTRAM -tramadol hydrochloride tablet, coated. Updated 07/2014. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=45f59e6f-1794-40a4-8f8b-3a9415924468. Accessed March 18, 2015.

[15] Drug Enforcement Administration, Office of Diversion Control. Tramadol. July 2014. http://www.deadiversion.usdoj.gov/drug_chem_info/tramadol.pdf.

[16] Nelson LS, Juurlink DN. Tramadol and hypoglycemia — one more thing to worry about. JAMA Intern Med. 2015;175(2):194-195. doi:10.1001/jamainternmed.2014.5260.Conflict.

[17] Fournier J-P, Azoulay L, Yin H, Montastruc J-L, et al. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med. 2015;175(2):186-193. doi:10.1001/jamainternmed.2014.6512.

[18] Bourne C, Gouraud A, Daveluy A, et al; French Association of Regional Pharmacovigilance Centres. Tramadol and hypoglycemia: Comparison with other step 2 analgesic drugs. Br J Clin Pharmacol. 2013;75(4):1063-1067.