Tramadol Reconsidered: Limited Benefit, Real Risk, and a Narrowing Role in Older Adults

Tramadol Reconsidered: Limited Benefit, Real Risk, and a Narrowing Role in Older Adults

By Ronald Rosen, MD, CWSP, CMD

Tramadol has long been regarded by clinicians in post-acute and long-term care as a comparatively “safer opioid,” appropriate when acetaminophen is insufficient and stronger opioids appear disproportionate. This reputation has been based on its dual mechanism pharmacologic profile and the assumption that it delivers effective analgesia with a lower risk of serious adverse effects than conventional opioids. However, emerging evidence no longer supports this assumption.

New systematic reviews, including a high-profile analysis published in BMJ Evidence-Based Medicine¹, suggest that tramadol provides only modest pain relief—often below clinically meaningful thresholds—while increasing the risk of adverse events. For older adults, particularly those in PALTC settings, this shifts the risk–benefit balance in an unfavorable direction. 

Pharmacology: Why Tramadol Is Different

Tramadol’s analgesic effects arise from two mechanisms:

1. Weak μ-opioid receptor agonism
2. Inhibition of serotonin and norepinephrine reuptake

This “dual-acting” profile was thought to broaden analgesic efficacy, particularly for mixed nociceptive and neuropathic pain, while reducing opioid-related harms. However, tramadol’s opioid activity depends on hepatic metabolism via CYP2D6 to its active metabolite (O-desmethyltramadol).

The pattern of reduced hepatic clearance, polypharmacy, and genetic variability in CYP2D6, commonly seen in older adults, leads to unpredictable efficacy and toxicity. Some patients experience little analgesia, while others develop sedation, delirium, or seizures at standard doses.² This variability undermines tramadol’s perceived reliability as a “middle-ground” analgesic.

Effectiveness: How Much Better Than Acetaminophen?

Acetaminophen remains first-line therapy for pain in older adults due to its predictable benefit and favorable safety profile when appropriately dosed. The maximum recommended dose is 3 gm/24 hours.

Tramadol is often assumed to offer superior pain control, but recent evidence suggests the incremental benefit, compared to acetaminophen, is small:¹

• A BMJ Evidence-Based Medicine systematic review and meta-analysis of randomized, placebo-controlled trials found that tramadol produced small reductions in chronic pain, frequently below thresholds patients consider clinically meaningful
• Improvements in physical function were minimal or absent.
• Rates of discontinuation due to adverse effects were significantly higher with tramadol than with a placebo

In practical terms, the difference in analgesic benefit between tramadol and acetaminophen is often modest, whereas the difference in risk is substantial.

Risk Profile: Particularly Relevant in PALTC Settings

Tramadol’s adverse effects are well documented and especially consequential in older adults:

Common adverse effects

• Nausea
• Dizziness
• Constipation
• Somnolence

Geriatric-specific risks

• Falls and fractures due to sedation and orthostasis
• Delirium, particularly in patients with baseline cognitive impairment
• Seizures, even at therapeutic doses
• Serotonin syndrome when combined with SSRIs, SNRIs, TCAs, bupropion, or other serotonergic agents
• Dependence and withdrawal, despite perceptions of lower abuse potential

Observational studies have also associated tramadol with higher all-cause mortality compared with NSAIDs in osteoarthritis populations, raising further concern about long-term use in older adults.

Reframing the Risk–Benefit Balance

The emerging evidence does not suggest that tramadol is ineffective. Rather, it indicates that:

• Analgesic benefits are modest, especially for chronic pain
• Adverse effects are frequent and clinically meaningful
• Superior safety over other opioids is increasingly difficult to justify

For PALTC clinicians, tramadol should not be viewed as a routine step-up from acetaminophen.

When—If Ever—Should Tramadol Be Used?

Based on current evidence, tramadol’s role should be limited, intentional, and time-bound.

Reasonable Circumstances

• Acute, moderate pain
• Failure of or contraindication to acetaminophen and NSAIDs
• Short-term use with a clearly defined stop date
• Low risk for delirium, falls, seizures, and drug–drug interactions in patients without pharmacogenic predispositions, i.e., not an ultrarapid metabolizer of CYP2D6 (higher risk of ADEs) or a poor metabolizer of CYP2D6 (unlikely to be effective)

Situations to Generally Avoid

• Chronic non-cancer pain
• Frailty or cognitive impairment
• Polypharmacy involving serotonergic medications
• Use driven primarily by the perception that tramadol is “safer than other opioids” and is significantly more effective than acetaminophen as an analgesic

Prescribing Pearls

• “Dual acting” does not mean dual benefit—it often means dual risk
• Avoid tramadol in patients with unexplained falls, fluctuating cognition, or seizure history
• Review medication lists carefully for serotonergic agents\
• Poor response may reflect CYP2D6 poor metabolizer status, not underdosing—dose escalation increases harm
• For chronic pain, prioritize non-pharmacologic strategies and condition-specific treatments rather than continuing tramadol

Conclusion

Tramadol’s reputation as a “gentle opioid” is increasingly unsupported by evidence. New data suggest limited analgesic benefit paired with disproportionate risk, particularly in older adults receiving post-acute or long-term care.

For PALTC clinicians, tramadol should be used sparingly, briefly, and deliberately—or not at all. In an era focused on deprescribing, safety, and meaningful outcomes, tramadol warrants careful reconsideration rather than routine use.

Selected References
1.    Häuser W, Petzke F, Radbruch L, Tölle TR. Efficacy, tolerability, and safety of tramadol for chronic pain: a systematic review and meta-analysis of randomized controlled trials. BMJ Evid Based Med. 2024;29(1):e000846.
2.    TRAMADOL HYDROCHLORIDE. FDA Drug Label, Food and Drug Administration. Updated date: 2025-11-20.

3.    Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long-term opioid treatment of chronic pain. JAMA. 2015;314(14):1474-1483. doi:10.1001/jama.2015.13085
4.    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. doi:10.1001/jama.2019.1347
5.    Pergolizzi JV Jr, Raffa RB, Taylor R Jr, et al. Tramadol: pharmacology, side effects, and serotonin syndrome. Pain Pract. 2015;15(2):145-156. doi:10.1111/papr.12185
6.    American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2023 updated Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2084. doi:10.1111/jgs.18372

Dr. Rosen is a geriatrician at Mass General Brigham and a hospice and palliative medicine physician at Care Dimensions Hospice and Palliative Care. He is a certified wound specialist and serves on the PALTmed Core Curriculum faculty.