[131] Tramadol: Where do we go from here?

[131] Tramadol: Where do we go from here?

Tramadol was marketed as an opioid analgesic in Germany in 1977, but not licenced in Canada until 2005. Health Canada has announced that it will add tramadol to Schedule I of the Controlled Drugs and Substances Act and to the Narcotic Control Regulations in March 2022.1 In Africa and the Middle East, abuse of tramadol is a recognized international crisis, in part because of its marketing as a “safer opioid.”2,3,4

Starting in 2007, the Canadian Drug Expert Committee recommended against reimbursement of tramadol because its costs exceeded alternatives.5 Tramadol’s unpredictability, unique potential harms, and lack of advantage over other opioids or NSAIDs are now well recognized.6

Clinical pharmacology

Beyond its opioid effect, tramadol is believed to modulate pain by inhibition of serotonin and norepinephrine reuptake.7,8 In vitro, it has weak affinity for mu-opioid receptors,9 but in humans the active metabolite O-desmethyltramadol (“M1”) is as potent as codeine.10 Biotransformation depends on the liver enzyme CYP2D6, whose activity varies between individuals and ethnic groups.11 About 5-10% of people are poor metabolizers,12 who experience mostly serotonergic and noradrenergic effects of tramadol (e.g. nausea, vomiting, dry mouth, agitation, restlessness, tremor, and muscle rigidity).13 Conversely, ultra-rapid metabolizers (1-2% of a population) are more prone to opioid effects including euphoria, respiratory depression and dependence, withdrawal, or overdose.12

How effective is tramadol?

Several Cochrane systematic reviews (SR) compared tramadol at up to 400mg/d with placebo or other analgesics. For osteoarthritis, a 2019 SR found “no important benefit” of tramadol (+/- acetaminophen) vs placebo for pain reduction by 20% from baseline or for improved physical function. Tramadol was less efficacious than NSAIDs for pain reduction.14 For neuropathic pain, cancer pain, and pediatric post-operative pain, Cochrane SRs found no conclusive evidence in favour of tramadol.15, 16, 17

We conducted a new SR including 20 double-blind randomized clinical trials (RCTs) comparing tramadol (+/- acetaminophen) with other opioids, 12 with NSAIDs and 1 with acetaminophen, for adults with any type of pain.18 Heterogeneous measurement and reporting of patient-important outcomes (e.g. clinically meaningful pain reduction, quality of life, overall function, and development of drug dependence or abuse) precluded meta-analysis of these 33 RCTs. From individual trials we found no convincing advantage of tramadol compared with opioids or NSAIDs on any measure of efficacy.

Harms identified in RCTs

For serious adverse events (SAEs) our SR found no differences between tramadol (+/- acetaminophen) and other opioids or NSAIDs. There were no deaths during 6 short-term RCTs (N=3,329), but this cannot predict real world outcomes from any opioid. Non-fatal SAEs were numerically but not significantly greater from tramadol than other opioids [10 RCTs, N=2,137; Risk Ratio (RR): 1.35 (95% CI 0.43-4.20)] and from tramadol than NSAIDs [7 RCTs, N=2,794; RR: 1.24 (95% CI 0.38-4.06)]. People taking tramadol (+/- acetaminophen) were more likely than NSAID users to withdraw from a trial due to adverse events [9 RCTs, N=3,092; RR: 2.83 (95% CI 2.21-3.63)] or to withdraw in general. Compared with people taking NSAIDs, patients prescribed tramadol were more likely to experience any adverse event. Our finding that NSAIDs are better tolerated than tramadol is consistent with the findings of the relevant Cochrane review.14

Table 1: Adverse events associated with tramadol in observational studies


Observational evidence


The US FDA Adverse Event Reporting System reported that tramadol increased the incidence of hypoglycemia compared with other opioids or SSRIs.19 

A retrospective review of hospitalized patients identified hypoglycemia associated with tramadol in 47% of people with type 1 diabetes, 16% with type 2, and 5% of non-diabetics.20


A nested case-control study of US patients found that tramadol was more likely than codeine to be associated with seizures leading to an emergency department visit or hospitalization (OR 1.41, 95% CI 1.11 to 1.79).21


A UK population-based cohort study found that tramadol was twice as likely as codeine to cause hospitalization due to hyponatremia.22

Serotonin toxicity

Over the past 20 years, the FDA Adverse Event Reporting System has recorded 968 cases (98 fatal) of tramadol-associated serotonin toxicity.23 Morphine, codeine, and opioids other than meperidine, methadone, and fentanyl do not precipitate serotonin toxicity.24

Dependence and withdrawal

As for other opioids, the Canadian product monographs for tramadol include a serious warning of addiction, abuse, misuse, overdose, and death.25 The WHO Expert Committee on Drug Dependence concluded that tramadol incurs a risk of addiction similar to other opioids such as morphine.26 One observational cohort study of 357,844 post-operative patients in the U.S. showed that compared with other opioids, patients given tramadol had similar or higher likelihood of prolonged opioid use.27 A U.S. population study found that 1 year after its initial prescription, 14% of people who received tramadol were still taking an opioid, vs 5-9% of those prescribed a different short-acting opioid.28

In addition to typical opioid withdrawal symptoms, tramadol withdrawal can include hallucinations, paranoia, anxiety, confusion, and unusual sensory experiences.29 Addiction vigilance data from France indicate that use of tramadol/acetaminophen is linked with fear of withdrawal, cravings, or desire for a psychoactive effect beyond pain relief, such as stimulation, euphoria, anxiolysis, or sedation.30

Utilization in BC

In 2020, 147,520 British Columbians received at least one prescription for tramadol (any formulation).31 Approximately 70% of post-operative patients in Canada are prescribed opioids, of which 19% are for tramadol or tramadol-acetaminophen. In contrast, only about 11% of Swedish post-operative patients receive any opioids.32


Tramadol is not covered by Pharmacare, the Palliative Care Benefits Plan, or any other public drug plans in BC.33 This reflects Common Drug Review recommendations against public funding of tramadol. In 2020 BC private health insurers and individuals spent $13.4 million on tramadol.31 IR tramadol is significantly more expensive than the equivalent dose of IR codeine or morphine (Table 2). Slow-release formulations of tramadol are much more expensive than SR morphine.34

Table 2: Cost of 3 IR opioids in BC

Drug formulation (IR)

Cost per tablet

Tramadol 37.5mg + acetaminophen31

$0.67 – $1.69

Codeine 30mg + acetaminophen34

$0.10 – $0.18

Morphine sulphate 5mg34



  • Compared with acetaminophen, NSAIDs or other opioids, tramadol has no therapeutic advantage but some disadvantages.
  • Tramadol’s unpredictable metabolism and complex pharmacology are associated with unique and serious adverse effects.
  • As with other opioids, even short prescriptions for tramadol can engender tolerance, dependence, withdrawal, and abuse.
  • Tramadol (+/- acetaminophen) significantly increases costs to patients and insurers.
The draft of this Therapeutics Letter was submitted for review to over 130 experts and primary care physicians in order to correct any inaccuracies and to ensure that the information is concise and relevant to clinicians.
The Therapeutics Initiative is funded by the BC Ministry of Health. The Therapeutics Initiative provides evidence-based advice about drug therapy, and is not responsible for formulating or adjudicating provincial drug policies.
ISSN: 2369-8691 (Online) || ISSN: 2369-8683 (Print)
International Society of Drug Bulletin LogoThe Therapeutics Letter is a member of the International Society of Drug Bulletins (ISDB), a world-wide network of independent drug bulletins that aims to promote international exchange of quality information on drugs and therapeutics.


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  2. Associated Press. How Tramadol, Touted as Safer Opioid, Became 3rd World Peril. 2019 Dec 13. https://www.usnews.com/news/business/articles/2019-12-13/another-opioid-crisis-is-raging-through-the-developing-world
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  12. World Health Organization. Tramadol: Update Review Report Agenda item 6.1. Expert Committee on Drug Dependence Thirty‐sixth Meeting. Geneva, 16‐20 June 2014 https://www.who.int/medicines/areas/quality_safety/6_1_Update.pdf
  13. Beakley B. Kaye AM, Kaye AD. Tramadol, Pharmacology, Side Effects, and Serotonin Syndrome: A Review. Pain Physician. 2015;18(4):395-400. https://www.painphysicianjournal.com/current/pdf?article=MjM3OA%3D%3D&journal=89
  14. Toupin AK, Bisaillon J, Welch V, et al. Tramadol for osteoarthritis. Cochrane Database of Systematic Reviews 2019, Issue 5. Art. No.: CD005522. DOI: 10.1002/14651858.CD005522.pub3
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  16. Wiffen PJ, Derry S, Moore R. Tramadol with or without paracetamol (acetaminophen) for cancer pain. Cochrane Database of Systematic Reviews 2017, Issue 5. Art. No.: CD012508. DOI: 10.1002/14651858.CD012508.pub2
  17. Schnabel A, Reichl SU, Meyer-Frießem C, et al. Tramadol for postoperative pain treatment in children. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD009574. DOI: 10.1002/14651858.CD009574.pub2
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  • Kirsten Myhr
    Posted at 11:23h, 14 July Reply

    Thank you for doing this review. I have been concerned about tramadol for many years and participated in a documentary for Danish TV in 2017. At that time I collected a lot of references and went into depth about the reports from the WHO committee on drug dependence. So coloured by the industry view (Grunenthal) that it is really a shame. Not the only time WHO had conflicts of interest though. Sadly, regulators move slowly to get rid of this useless and toxic medicine.
    My interest arose when I worked at a medicines information centre in Norway and got involved in a court case as a witness. I’ve later heard of old people recovering so well that they could leave nursing homes after having discontinued the drug. I think the widespread use here was caused by tramadol not being on the narcotics list and thus less restricted and the orthopedic surgeons using it after e.g. hip replacement surgery. I myself managed to avoid getting it for that!
    I see you refer to the metabolism. It is also worth mentioning that there are ethnic differences in the CYP2D6 metabolism and so certain populations e.g. in the middle east and east Africa might have up to 30% poor metabolizers.

    • Jessica Otte
      Posted at 13:30h, 14 July Reply

      Thank you for your comments, Kirsten.
      Yes, the CYP P450 variations tend to be more prominent in certain ethnic groups; because an individual patient’s particular genetic compliment is not known at the time of prescribing (except in rare cases where their metabolism is tested), it is important for clinicians to know that the metabolism of the drug is not predictable.
      The WHO initially included “weak opioids” on their initial analgesic ladder (https://www.ncbi.nlm.nih.gov/books/NBK554435/). That organization has since explored the non-medical use, public health issues, illicit manufacture, and other challenges that have arisen in relation to this drug (https://www.who.int/medicines/access/controlled-substances/Tramadol.pdf).
      Interestingly, it looks like there is a publication that assesses the effects of the 2017 Danish media attention on this drug: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935826/

      • Kirsten Myhr
        Posted at 12:03h, 15 July Reply

        Thank you. I’m not following tramadol so closely anymore and wasn’t aware of the Danish study so great to get the reference. I’m a retired pharmacist that spent the last 15 years until 2016 as head of a regional pharmacovigilance and drug information centre in Oslo (www.relis.no ). 2013-2019 I was alternate member representing European healthcare professionals in the EMA’s Pharmacovigilance Risk Assessment Committee. So drug safety is still something I follow closely, though at present my focus is on access to medicines globally.
        I think that the term ‘weak opioid’ should never have been introduced and in particular the company should not have been allowed to say that tramadol didn’t have the same dependence potential as other opioids.
        Thanks again for the article.

  • Jose A. Tous Olagorta
    Posted at 04:04h, 16 July Reply

    Congratulations! Excellent information!
    Please read this reference if you don’t know it (and enjoy a good laugh): https://emcrit.org/toxhound/tramadont/
    I have been hoping (since the 1990’s) to see the end of tramadol prescribing, but it is very, very difficult to change medical thinking.
    Egreggio Dottore

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