Tramadol Safety

What is tramadol’s mechanism of action?

Tramadol is a synthetic codeine analog.¹ Tramadol acts, at least in part, through weak agonist activity at mu opioid receptors.¹ It is also a weak SNRI.⁹

What is tramadol’s abuse potential?

Tramadol has been available in the U.S. since 1995, but it did not become a controlled substance on the federal level until August 18, 2014.⁴ However, some states had already made it a controlled substance before then.⁴ Tramadol was placed in Schedule IV because available data suggested its abuse potential was similar to that of the Schedule IV opioid propoxyphene (no longer marketed), but lower than Schedule III drugs.⁴ Health Canada has also changed tramadol to controlled drug status, Schedule I, effective March 31, 2022.²³

At supratherapeutic doses, tramadol can produce subjective effects similar to morphine or oxycodone.⁴

There is no evidence that tramadol has less abuse potential than morphine at an equianalgesic morphine dose.¹⁹ Total daily dose-equivalencies suggested vary in the literature (e.g., 10:1 [tramadol 300 mg = morphine 30 mg]; Canadian labeling, 6:1 [tramadol 400 mg = morphine 66.7 mg]).^20,22 When converting, consider a conservative approach given the interindividual variation in tramadol response (discussed below).

In 2016, 1.6 million people misused tramadol.³ Tramadol is most often abused by narcotic addicts, chronic pain patients, and healthcare professionals.³

What are some general dosing considerations for tramadol?

The maximum total daily dose of tramadol is 300 to 400 mg, depending on the specific product.^5,12

Tramadol requires dose reduction in the elderly and in patients with renal impairment (CrCl <30 mL/min).¹⁵

• Avoid extended-release tramadol if CrCl <30 mL/min.¹⁵

A dose of 25 mg every eight hours can be considered with caution in patients with liver impairment.⁶

What are the risks of tramadol at normal or excessive doses?

In 2011, U.S. emergency departments handled 16,561 adverse reactions related to tramadol. This does not include tramadol in combination with other pharmaceuticals.¹⁴

In addition to the usual opioid toxicities such as CNS and respiratory depression, even when taken as prescribed, tramadol can result in seizures, hyponatremia, serotonin syndrome, and perhaps hypoglycemia.^3,5,8,13-16

• A sodium level should be checked when starting or changing the dose in the elderly.¹⁵
• The prevalence of tramadol-associated seizures is 0.15% to 0.86%.²¹ Most seizures occur with supratherapeutic doses in patients abusing tramadol, but doses as low as 100 mg have also been associated with seizures.²¹
• Comorbidities that increase seizure risk include seizure history, renal insufficiency, stroke, and brain trauma.²¹

In a case report of cardiotoxicity in a tramadol abuser, the patient was found to have a genetic anomaly (CYP2D6 ultrarapid metabolizer) associated with excessive production of tramadol’s active metabolite (M1).⁷ Although metabolizer phenotype information is not readily available in the clinical setting, this case underscores the importance of patients not exceeding the prescribed dose. Patients with ancestry from North Africa or the Arabian peninsula are most likely to have this phenotype.²¹

Hallucinations are reported in less than 1% of patients taking tramadol; however, there appears to be an increasing number of cases.  A Health Canada review establishes a link between normal doses of tramadol and hallucinations (visual and auditory), with an increased risk in patients 65 years and older.²⁶

Is tramadol safer than “pure” opioids such as oxycodone or morphine?

Tramadol response is subject to interpatient variability (due to differences in CYP2D6 activity),¹⁹ so it is difficult to generalize the relative safety of tramadol vs other opioids.

Because tramadol has SNRI-like effects in addition to opioid effects, it poses additional concerns as described above (e.g., hyponatremia, seizures, serotonin syndrome).¹⁹

Naloxone can be used to treat tramadol-associated respiratory depression.¹² Some, but not all, reports associate naloxone use with seizures in tramadol overdose.^12,24,25

Can tramadol be used in children or pregnant women?

Tramadol should generally not be used in children, pregnant women, and moms of breastfeeding infants. See our charts, Analgesics in Kids, FAQs and Analgesics in Pregnancy and Lactation, for details.

What are some tramadol interactions to watch out for?

Tramadol’s sedative effects and respiratory depressant effects are increased when combined with other CNS depressants such as benzodiazepine, muscle relaxants, antipsychotics, or alcohol.¹⁴

Tramadol is metabolized by CYP3A4, and to its active metabolite by CYP2D6.¹³ Poor metabolizers (patients who genetically lack CYP2D6 activity), and patients taking CYP2D6 inhibitors, can experience reduced tramadol analgesic efficacy.¹³ Get our chart, CYP450 Drug Interactions, for help identifying potential interactions.

Use with antidepressants that inhibit CYP2D6 and reduce seizure threshold (e.g., bupropion, venlafaxine, SSRIs), or in patients at risk of alcohol withdrawal, may increase the risk of seizures.¹⁷

The risk of serotonin syndrome with tramadol can be increased with use of other serotonergic drugs, such as antidepressants (e.g., citalopram, fluoxetine, fluvoxamine, mirtazapine, paroxetine, sertraline, tricyclic antidepressants, venlafaxine).^11,13,17 The interaction may be due to inhibition of tramadol metabolism in addition to serotonergic activity.¹³ Tramadol is contraindicated with or within 14 days of an MAOI.^5,12 For more information, see our chart, Facts About Serotonin Syndrome.

Does tramadol discontinuation require tapering?

Tramadol use has been associated with a withdrawal syndrome. In keeping with its dual mechanism of action, withdrawal symptoms can include opioid-like withdrawal symptoms (e.g., anxiety, restlessness, insomnia, sweating, goose bumps, pain, nausea, twitching, diarrhea, abdominal cramps, runny nose, autonomic symptoms), migraine-like headache, myoclonus, restless legs syndrome, and less commonly, atypical (SNRI-like) withdrawal symptoms (e.g., psychosis, extreme anxiety, panic, confusion, paresthesia).^2,5,9,10

No specific tapering regimen is suggested. Consider tapering as for opioids. See our chart, Opioid Tapering: Tips for Success, for help.

What is tramadol’s place in therapy?

Tramadol is not a first-line option for treatment of pain. It is not more effective than NSAIDs for acute injuries or back pain, and there is not much evidence it is effective for neuropathic pain or osteoarthritis. See our charts for alternatives for various types of pain:

• Analgesics for Osteoarthritis
  
• Analgesics for Acute Pain
  
• Treatment of Acute Low Back Pain
  
• Treatment of Chronic Low Back Pain
  
• Pharmacotherapy of Neuropathic Pain
  

What are some counseling points to cover with patients prescribed tramadol?

Patients prescribed tramadol should be warned not to take extra doses.⁹ Use the lowest necessary dose for as short a time as possible.⁹

Patients should be told not to use tramadol with alcohol or nonprescribed medications, including drugs of abuse.⁹

For patients at risk of serotonin syndrome, get our patient education handout, What You Should Know About Serotonin Syndrome.