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

14 Jul 2021 [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

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

Cost

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

Conclusions

• 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 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.

References

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