Association of Tramadol With All-Cause Mortality in Patients With Osteoarthritis | Clinical Pharmacy and Pharmacology | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

Association of Tramadol With All-Cause Mortality Among Patients With Osteoarthritis

Educational Objective
To review if tramadol prescription associated with a higher risk of all-cause mortality than other pain relief medications among patients with osteoarthritis?
1 Credit CME
Key Points

Question  Is tramadol prescription associated with a higher risk of all-cause mortality than other pain relief medications among patients with osteoarthritis?

Findings  In this cohort study that included 88 902 patients with osteoarthritis, initial prescription of tramadol was associated with a significantly increased risk of mortality over 1 year compared with initial prescription of naproxen (hazard ratio [HR], 1.71), diclofenac (HR, 1.88), celecoxib (HR, 1.70), and etoricoxib (HR, 2.04), but not compared with codeine (HR, 0.94).

Meaning  Tramadol prescription may be associated with increased all-cause mortality compared with commonly prescribed nonsteroidal anti-inflammatory drugs, but further research is needed to determine if this relationship is causal.

Abstract

Importance  An American Academy of Orthopaedic Surgeons guideline recommends tramadol for patients with knee osteoarthritis, and an American College of Rheumatology guideline conditionally recommends tramadol as first-line therapy for patients with knee osteoarthritis, along with nonsteroidal anti-inflammatory drugs.

Objective  To examine the association of tramadol prescription with all-cause mortality among patients with osteoarthritis.

Design, Setting, and Participants  Sequential, propensity score–matched cohort study at a general practice in the United Kingdom. Individuals aged at least 50 years with a diagnosis of osteoarthritis in the Health Improvement Network database from January 2000 to December 2015, with follow-up to December 2016.

Exposures  Initial prescription of tramadol (n = 44 451), naproxen (n = 12 397), diclofenac (n = 6512), celecoxib (n = 5674), etoricoxib (n = 2946), or codeine (n = 16 922).

Main Outcomes and Measures  All-cause mortality within 1 year after initial tramadol prescription, compared with 5 other pain relief medications.

Results  After propensity score matching, 88 902 patients were included (mean [SD] age, 70.1 [9.5] years; 61.2% were women). During the 1-year follow-up, 278 deaths (23.5/1000 person-years) occurred in the tramadol cohort and 164 (13.8/1000 person-years) occurred in the naproxen cohort (rate difference, 9.7 deaths/1000 person-years [95% CI, 6.3-13.2]; hazard ratio [HR], 1.71 [95% CI, 1.41-2.07]), and mortality was higher for tramadol compared with diclofenac (36.2/1000 vs 19.2/1000 person-years; HR, 1.88 [95% CI, 1.51-2.35]). Tramadol was also associated with a higher all-cause mortality rate compared with celecoxib (31.2/1000 vs 18.4/1000 person-years; HR, 1.70 [95% CI, 1.33-2.17]) and etoricoxib (25.7/1000 vs 12.8/1000 person-years; HR, 2.04 [95% CI, 1.37-3.03]). No statistically significant difference in all-cause mortality was observed between tramadol and codeine (32.2/1000 vs 34.6/1000 person-years; HR, 0.94 [95% CI, 0.83-1.05]).

Conclusions and Relevance  Among patients aged 50 years and older with osteoarthritis, initial prescription of tramadol was associated with a significantly higher rate of mortality over 1 year of follow-up compared with commonly prescribed nonsteroidal anti-inflammatory drugs, but not compared with codeine. However, these findings may be susceptible to confounding by indication, and further research is needed to determine if this association is causal.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Corresponding Authors: Guanghua Lei, MD, PhD, Department of Orthopaedics, Xiangya Hospital, Central South University, 87 Xiangya Rd, Changsha, Hunan 410008, China (lei_guanghua@csu.edu.cn); Yuqing Zhang, DSc, Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA 02114 (yzhang108@mgh.harvard.edu).

Accepted for Publication: February 5, 2019.

Author Contributions: Dr Zhang had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Lei and Zhang are joint corresponding authors.

Concept and design: Zeng, Dubreuil, Lu, Choi, Lei, Zhang.

Acquisition, analysis, or interpretation of data: Zeng, Dubreuil, Larochelle, Lu, Wei, Lei, Zhang.

Drafting of the manuscript: Zeng, Lu, Choi, Lei, Zhang.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Lu, Wei, Choi, Zhang.

Obtained funding: Zeng, Wei, Choi, Lei, Zhang.

Administrative, technical, or material support: Zeng, Wei, Choi, Lei, Zhang.

Supervision: Choi, Lei, Zhang.

Conflict of Interest Disclosures: Dr Larochelle reported receiving grants from National Institute on Drug Abuse (K23 DA042168) during the conduct of the study and grants from Optum Labs outside the submitted work. No other disclosures were reported.

Funding/Support: This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (K23 AR069127, P60 AR047785), and the National Natural Science Foundation of China (81772413, 81702207, 81702206).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The interpretation of these data is the sole responsibility of the authors.

References
1.
Glyn-Jones  S, Palmer  AJ, Agricola  R,  et al.  Osteoarthritis.  Lancet. 2015;386(9991):376-387. doi:10.1016/S0140-6736(14)60802-3PubMedGoogle ScholarCrossref
2.
Hassamal  S, Miotto  K, Dale  W, Danovitch  I.  Tramadol: understanding the risk of serotonin syndrome and seizures.  Am J Med. 2018;131(11):1382.e1-1382.e6. doi:10.1016/j.amjmed.2018.04.025PubMedGoogle ScholarCrossref
3.
Jevsevar  DS.  Treatment of osteoarthritis of the knee:evidence-based guideline, 2nd edition.  J Am Acad Orthop Surg. 2013;21(9):571-576. doi:10.5435/JAAOS-21-09-571PubMedGoogle Scholar
4.
Hochberg  MC, Altman  RD, April  KT,  et al; American College of Rheumatology.  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. doi:10.1002/acr.21596PubMedGoogle ScholarCrossref
5.
Wright  EA, Katz  JN, Abrams  S, Solomon  DH, Losina  E.  Trends in prescription of opioids from 2003-2009 in persons with knee osteoarthritis.  Arthritis Care Res (Hoboken). 2014;66(10):1489-1495. doi:10.1002/acr.22360PubMedGoogle ScholarCrossref
6.
Smith  SR, Deshpande  BR, Collins  JE, Katz  JN, Losina  E.  Comparative pain reduction of oral non-steroidal anti-inflammatory drugs and opioids for knee osteoarthritis: systematic analytic review.  Osteoarthritis Cartilage. 2016;24(6):962-972. doi:10.1016/j.joca.2016.01.135PubMedGoogle ScholarCrossref
7.
Beaulieu  AD, Peloso  PM, Haraoui  B,  et al.  Once-daily, controlled-release tramadol and sustained-release diclofenac relieve chronic pain due to osteoarthritis: a randomized controlled trial.  Pain Res Manag. 2008;13(2):103-110. doi:10.1155/2008/903784PubMedGoogle ScholarCrossref
8.
Solomon  DH, Rassen  JA, Glynn  RJ,  et al.  The comparative safety of opioids for nonmalignant pain in older adults.  Arch Intern Med. 2010;170(22):1979-1986. doi:10.1001/archinternmed.2010.450PubMedGoogle ScholarCrossref
9.
Tørring  ML, Riis  A, Christensen  S,  et al.  Perforated peptic ulcer and short-term mortality among tramadol users.  Br J Clin Pharmacol. 2008;65(4):565-572. doi:10.1111/j.1365-2125.2007.03038.xPubMedGoogle ScholarCrossref
10.
Kimmel  PL, Fwu  CW, Abbott  KC, Eggers  AW, Kline  PP, Eggers  PW.  Opioid prescription, morbidity, and mortality in United States dialysis patients.  J Am Soc Nephrol. 2017;28(12):3658-3670. doi:10.1681/ASN.2017010098PubMedGoogle ScholarCrossref
11.
Härstedt  M, Rogmark  C, Sutton  R, Melander  O, Fedorowski  A.  Polypharmacy and adverse outcomes after hip fracture surgery.  J Orthop Surg Res. 2016;11(1):151. doi:10.1186/s13018-016-0486-7PubMedGoogle ScholarCrossref
12.
Burr  NE, Smith  C, West  R, Hull  MA, Subramanian  V.  Increasing prescription of opiates and mortality in patients with inflammatory bowel diseases in England.  Clin Gastroenterol Hepatol. 2018;16(4):534-541.e6. doi:10.1016/j.cgh.2017.10.022PubMedGoogle ScholarCrossref
13.
Chen  TC, Chen  LC, Knaggs  RD.  A 15-year overview of increasing tramadol utilisation and associated mortality and the impact of tramadol classification in the United Kingdom.  Pharmacoepidemiol Drug Saf. 2018;27(5):487-494. doi:10.1002/pds.4320PubMedGoogle ScholarCrossref
14.
Seeger  JD, Williams  PL, Walker  AM.  An application of propensity score matching using claims data.  Pharmacoepidemiol Drug Saf. 2005;14(7):465-476. doi:10.1002/pds.1062PubMedGoogle ScholarCrossref
15.
Lin  DY, Wei  LJ, Ying  Z.  Checking the Cox model with cumulative sums of Martingale based residuals.  Biometrika. 1993;80:557-572. doi:10.1093/biomet/80.3.557Google ScholarCrossref
16.
Stürmer  T, Rothman  KJ, Avorn  J, Glynn  RJ.  Treatment effects in the presence of unmeasured confounding: dealing with observations in the tails of the propensity score distribution--a simulation study.  Am J Epidemiol. 2010;172(7):843-854. doi:10.1093/aje/kwq198PubMedGoogle ScholarCrossref
17.
Rubin  DB.  Multiple Imputation for Nonresponse in Surveys. New York, NY: John Wiley & Sons; 1987. doi:10.1002/9780470316696
18.
Hicks  BM, Filion  KB, Yin  H, Sakr  L, Udell  JA, Azoulay  L.  Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study.  BMJ. 2018;363:k4209. doi:10.1136/bmj.k4209PubMedGoogle ScholarCrossref
19.
Ogdie  A, Maliha  S, Shin  D,  et al.  Cause-specific mortality in patients with psoriatic arthritis and rheumatoid arthritis.  Rheumatology (Oxford). 2017;56(6):907-911. doi:10.1093/rheumatology/kew502PubMedGoogle ScholarCrossref
20.
Solomon  DH, Rassen  JA, Glynn  RJ, Lee  J, Levin  R, Schneeweiss  S.  The comparative safety of analgesics in older adults with arthritis.  Arch Intern Med. 2010;170(22):1968-1976. doi:10.1001/archinternmed.2010.391PubMedGoogle ScholarCrossref
21.
Dart  RC, Surratt  HL, Cicero  TJ,  et al.  Trends in opioid analgesic abuse and mortality in the United States.  N Engl J Med. 2015;372(3):241-248. doi:10.1056/NEJMsa1406143PubMedGoogle ScholarCrossref
22.
Ray  WA, Chung  CP, Murray  KT, Hall  K, Stein  CM.  Prescription of long-acting opioids and mortality in patients with chronic noncancer pain.  JAMA. 2016;315(22):2415-2423. doi:10.1001/jama.2016.7789PubMedGoogle ScholarCrossref
23.
Katz  WA.  Pharmacology and clinical experience with tramadol in osteoarthritis.  Drugs. 1996;52(suppl 3):39-47. doi:10.2165/00003495-199600523-00007PubMedGoogle ScholarCrossref
24.
Brouquet  A, Cudennec  T, Benoist  S,  et al.  Impaired mobility, ASA status and administration of tramadol are risk factors for postoperative delirium in patients aged 75 years or more after major abdominal surgery.  Ann Surg. 2010;251(4):759-765. doi:10.1097/SLA.0b013e3181c1cfc9PubMedGoogle ScholarCrossref
25.
Randall  C, Crane  J.  Tramadol deaths in Northern Ireland: a review of cases from 1996 to 2012.  J Forensic Leg Med. 2014;23:32-36. doi:10.1016/j.jflm.2014.01.006PubMedGoogle ScholarCrossref
26.
Handley  SA, Flanagan  RJ.  Drugs and other chemicals involved in fatal poisoning in England and Wales during 2000 – 2011.  Clin Toxicol (Phila). 2014;52(1):1-12. doi:10.3109/15563650.2013.872791PubMedGoogle ScholarCrossref
27.
Tjäderborn  M, Jönsson  AK, Hägg  S, Ahlner  J.  Fatal unintentional intoxications with tramadol during 1995-2005.  Forensic Sci Int. 2007;173(2-3):107-111. doi:10.1016/j.forsciint.2007.02.007PubMedGoogle ScholarCrossref
28.
Häkkinen  M, Launiainen  T, Vuori  E, Ojanperä  I.  Comparison of fatal poisonings by prescription opioids.  Forensic Sci Int. 2012;222(1-3):327-331. doi:10.1016/j.forsciint.2012.07.011PubMedGoogle ScholarCrossref
29.
Fournier  J-P, Azoulay  L, Yin  H, Montastruc  J-L, Suissa  S.  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.2014.6512PubMedGoogle ScholarCrossref
30.
Fournier  JP, Yin  H, Nessim  SJ, Montastruc  JL, Azoulay  L.  Tramadol for noncancer pain and the risk of hyponatremia.  Am J Med. 2015;128(4):418-425.e5. doi:10.1016/j.amjmed.2014.10.046Google ScholarCrossref
31.
Vestergaard  P, Rejnmark  L, Mosekilde  L.  Fracture risk associated with the use of morphine and opiates.  J Intern Med. 2006;260(1):76-87. doi:10.1111/j.1365-2796.2006.01667.xPubMedGoogle ScholarCrossref
32.
Costa-Dias  MJ, Oliveira  AS, Martins  T,  et al.  Medication fall risk in old hospitalized patients: a retrospective study.  Nurse Educ Today. 2014;34(2):171-176. doi:10.1016/j.nedt.2013.05.016PubMedGoogle ScholarCrossref
33.
McAlindon  TE, Bannuru  RR, Sullivan  MC,  et al.  OARSI guidelines for the non-surgical management of knee osteoarthritis.  Osteoarthritis Cartilage. 2014;22(3):363-388. doi:10.1016/j.joca.2014.01.003PubMedGoogle ScholarCrossref
34.
National Institute for Health and Care Excellence. Osteoarthritis: care and management. National Institute for Health and Care Excellence website. https://www.nice.org.uk/guidance/cg177. Published February 2014. Accessed June 21, 2017.
35.
Latimer  N, Lord  J, Grant  RL, O’Mahony  R, Dickson  J, Conaghan  PG; National Institute for Health and Clinical Excellence Osteoarthritis Guideline Development Group.  Cost effectiveness of COX 2 selective inhibitors and traditional NSAIDs alone or in combination with a proton pump inhibitor for people with osteoarthritis.  BMJ. 2009;339:b2538. doi:10.1136/bmj.b2538PubMedGoogle ScholarCrossref
36.
Katz  JN, Smith  SR, Collins  JE,  et al.  Cost-effectiveness of nonsteroidal anti-inflammatory drugs and opioids in the treatment of knee osteoarthritis in older patients with multiple comorbidities.  Osteoarthritis Cartilage. 2016;24(3):409-418. doi:10.1016/j.joca.2015.10.006PubMedGoogle ScholarCrossref
37.
Scarpignato  C, Lanas  A, Blandizzi  C, Lems  WF, Hermann  M, Hunt  RH; International NSAID Consensus Group.  Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis--an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks.  BMC Med. 2015;13:55. doi:10.1186/s12916-015-0285-8PubMedGoogle ScholarCrossref
38.
Dowell  D, Haegerich  TM, Chou  R.  CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016.  JAMA. 2016;315(15):1624-1645. doi:10.1001/jama.2016.1464PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close