TRAMADOL: BALANCING PAIN RELIEF AND SAFETY IN CLINICAL PRACTICE

Faculty:

L. Austin Fredrickson, MD, FACP 

L. Austin Fredrickson is an Associate Professor of Internal Medicine at Northeast Ohio Medical University, where he serves as core faculty and teaches diagnostics, therapeutics, clinical skills, and health humanities. He is board-certified in general internal medicine and practices rural primary care. 

Sandra Rogers, MD

Sandra Rogers is a primary care physician in Texas. She is board-certified through the American Board of Family Medicine and the American Board of Internal Medicine. She completed her dual residency at Eastern Virginia Medical School in Norfolk, Virginia. She has been practicing in Allen, Texas, for over 20 years.

Kelsey Giara, PharmD, RPh

Kelsey Giara is a pharmacist and freelance medical writer based in New Hampshire. She writes about a variety of healthcare topics for various publications and has significant experience in continuing medical education, needs assessments, grant writing, and medical communications.

Pamela Sardo, PharmD, BS

Pamela Sardo is a freelance medical writer, licensed pharmacist, and the founder/principal at Sardo Solutions. She received her BS from the University of Connecticut and a PharmD from the University of Rhode Island. Pam’s career spans many years in retail, clinics, hospitals, long-term care, Veterans Affairs, pharmaceutical manufacturing, and managed healthcare across broad therapeutic classes and disease states.

Abstract

Tramadol is a synthetic, schedule IV opioid. Tramadol is called a weak opioid because it was initially compared to hydromorphone and morphine. Although it began as a non-controlled analgesic when first marketed in the US, reports of misuse and diversion led to a change in labeling. By 2014, tramadol became a Schedule IV drug. It is now known that tramadol can lead to a substance use disorder and cause serious morbidities and death. It should be used cautiously because tramadol can cause sedation and other physical side effects. Abrupt cessation of tramadol can lead to withdrawal symptoms like other opioids. Dosing adjustments should be made for patients with hepatic and renal conditions, with ongoing monitoring of the patient’s response and progress. Tramadol should be avoided or used with caution in patients with a history of mental illness and a history or risk of a substance use disorder. Although said to be a weak opioid, tramadol use disorder is a real risk, and it can be a dangerous drug when taken in excess of therapeutic levels.

Accreditation Statements

In support of improving patient care, RxCe.com LLC is jointly accredited by the Accreditation CouncilTM for Continuing Medical Education (ACCMEÂŽ), the Accreditation Council for Pharmacy Education (ACPEÂŽ), and the American Nurses Credentialing Center (ANCCÂŽ), to provide continuing education for the healthcare team.

This activity was planned by and for the healthcare team, and learners will receive 3 Interprofessional Continuing Education (IPCE) credit for learning and change.

Joint Universal Activity Number: The Joint Accreditation Universal Activity Numbers assigned to this activity are as follows:

Pharmacists: JA4008424-0000-26-021-H01-P

Pharmacy Technicians: JA4008424-0000-26-021-H01-T

Credits: 3 contact hour(s) (0.3 CEU(s)) of continuing education credit.

Credit Types:

IPCE Credits - 3 Credits

AAPA Category 1 Credit™️ - 3 Credits

AMA PRA Category 1 Credit™️ - 3 Credits

Pharmacy - 3 Credits

Type of Activity: Knowledge and Application

Media: Computer-Based Training (i.e., online courses)

Estimated time to complete activity: 3 contact hour(s) (0.3 CEU(s)), including Course Test and course evaluation.

Release Date: March 2, 2026 Expiration Date: March 2, 2029

Target Audience: This educational activity is for Physicians, Physician Assistants, Pharmacists, and Pharmacy Technicians

How to Earn Credit: From March 2, 2026, through March 2, 2029, participants must:

Read the “learning objectives” and “author and planning team disclosures;”

Take the “Educational Activity Pre-Test;”

Study the section entitled “Educational Activity;” and

Complete the Educational Activity Post-Test and Activity Evaluation. The Educational Activity Post-Test will be graded automatically. Following successful completion of the Educational Activity Post-Test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)

CME Credit: Credit for this course will be uploaded to CPE Monitor® for pharmacists. Physicians may receive AMA PRA Category 1 Credit™️ and use these credits toward Maintenance of Certification (MOC) requirements. Physician Assistants may earn AAPA Category 1 CME credit, reportable through PA Portfolio. All learners shall verify their individual licensing board’s specific requirements and eligibility criteria.

Statement of Need

Tramadol is widely prescribed in the US and worldwide. Its historical popularity was partly due to its perceived favorable side effects profile and safety, and the perception that it was less likely to be misused than other short-acting opioids; however, tramadol may be just as misused as other opioids. Education is needed to clarify tramadol’s clinical use, reinforce safety procedures, and reinforce measures that healthcare professionals may take to prevent misuse and overdose. This activity aims to align current evidence and practice, promote appropriate dosing, monitoring, and support patient-centered decision-making to enhance safety and outcomes in clinical settings.

Learning Objectives: Upon completion of this educational activity, participants should be able to:

Describe the basic pharmacological profile, use, and clinical outcomes of tramadol treatment

Identify the dosing for tramadol for the treatment of acute and long-term pain

Compare the benefits and risks of tramadol compared to other drugs used to treat acute and long-term pain

Identify the contraindications and potential side effects of tramadol

Disclosures

The following individuals were involved in planning, developing, and/or authoring this activity: L. Austin Fredrickson, MD, FACP; Sandra Rogers, MD; Kelsey Giara, PharmD, RPh; and Pamela Sardo, PharmD, BS. None of the individuals involved in developing this activity has a conflict of interest or financial relationships related to the subject matter. There are no financial relationships or commercial or financial support relevant to this activity to report or disclose by RxCe.com or any of the individuals involved in the development of this activity. 

Š RxCe.com LLC 2026: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.

Educational Activity Pre-Test

Tramadol is contraindicated in which population?

Children younger than 12 years of age

Adolescents 12 to 18 years old with obesity

Adolescents 12 to 18 years old with obstructive sleep apnea

Adults and children with chronic pulmonary disease

Which of the following patients is at the highest risk of tramadol-induced seizures?

A patient taking acetaminophen

A patient with controlled hypertension

A patient with alcohol withdrawal

A patient with mild GERD

According to the 2023 AGS Beers Criteria, tramadol should be used cautiously in older adults primarily due to the risk of

hyperkalemia.

hyponatremia/SIADH.

hypotension.

Parkinson-like symptoms.

Educational Activity

Tramadol: Balancing Pain Relief and Safety in Clinical Practice

Introduction

Tramadol is a synthetic, Schedule IV opioid used to treat acute and chronic pain and for perioperative pain management. Although widely prescribed in the United States (US) and globally, its popularity has often been driven by the perception that tramadol carries a more favorable safety profile and lower misuse potential than other short-acting opioids. Emerging evidence, however, shows that tramadol can be misused to a similar extent as other opioids, challenging these long-held assumptions.

When used appropriately, tramadol can provide meaningful pain relief and improved patient outcomes. Yet its unique pharmacologic properties—including combined μ-opioid receptor activity and monoamine reuptake inhibition—also introduce important safety considerations. Tramadol is not suitable for all patient populations, requires individualized dosing in some cases, and can contribute to accidental overdose, particularly when drug interactions, metabolic variability, or supratherapeutic dosing are involved. Such overdoses may result in serious morbidity or death, underscoring the need for primary care physicians and other members of the healthcare team to understand both the benefits and the risks associated with this commonly prescribed medication.

Clinical Overview of Tramadol

Opiates are naturally occurring compounds derived from the opium poppy plant, Papaver somniferum, with codeine and morphine being the two principal compounds prescribed in clinical practice.1 Semi-synthetic or synthetic opioids are also available. A semi-synthetic opioid is a derivative of a natural opiate. For example, heroin is a semi-synthetic opioid derived from morphine.1 In contrast, synthetic opioids are not derived from opiates; they are made in a laboratory and designed to mimic natural opioids.2 Tramadol is an example of a synthetic opioid that mimics naturally occurring codeine and produces opioid-like effects.3 Natural, semi-synthetic, and synthetic opioids bind specific opioid receptors to produce their effects. All opioids produce analgesia in varying duration and magnitude, depending on their pharmacokinetic and pharmacodynamic profiles.

History and Controlled Status

Tramadol was initially developed in Germany in the 1970s. In 1995, the US Food and Drug Administration (FDA) approved the drug as an atypical, weak opioid analgesic available by prescription but not controlled.4 After its FDA approval, tramadol’s popularity rose quickly because healthcare providers perceived it had a favorable adverse effect (AE) and safety profile, and also believed (mistakenly) that it was less likely to be misused than other short-acting opioids.4 In fact, several early studies exploring the risks associated with opioid use failed to include tramadol due to these false perceptions. The drug quickly became one of the most prescribed opioids in the US.4

As the opioid crisis grew and attracted more attention, the FDA revisited tramadol’s controlled substance status, changing it in 2014 to a Schedule IV controlled substance in the US.4,5 The FDA made this change based on a re-evaluation of its probability for misuse.5 Tramadol’s Schedule IV status indicates that it has a legitimate medical use with a low potential for the development of a substance use disorder (SUD).6 Other countries—including the United Kingdom and Canada—have also classified tramadol as a controlled substance.7

Some healthcare professionals wonder why tramadol is a schedule IV drug while other opioids, e.g., morphine and oxycodone, are schedule II drugs.4,6 This appears to be the result of tramadol’s reputation as a drug that has a lower propensity to lead to SUD than other opioids. This reputation was reflected in a 2018 randomized clinical trial that grouped tramadol with other “non-opioid medications.”8,9 The view that tramadol is less problematic than other controlled substances is evidenced by its continuing popularity as a prescription drug. Reports from the US Drug Enforcement Administration imply this as well: after tramadol’s classification as a controlled substance, tramadol prescriptions within the US have not dropped significantly.5

Pharmacologic Profile

Tramadol has unique characteristics when compared to conventional opioids, causing some medical researchers and clinicians to refer to tramadol as an “atypical” opioid with milder, opioid-like results. An opioid’s potency is typically determined by its relation to morphine’s potency and is described with the term “morphine milliequivalents,” or MMEs. Tramadol is considered a mild opioid, partially because a 50 mg tablet of tramadol is considered equivalent to 5 mg of morphine or having 5 MMEs.10-12 Because of its perceived pharmacologic safety, tramadol is widely used. It may be prescribed in different forms, and some recommendations and adjustments are available to guide primary care professionals who prescribe and administer the drug. Primary care physicians and other members of the healthcare team must also consider the warnings and adverse events that may be associated with tramadol’s use.9

Tramadol’s uniqueness begins with its mechanism of action.9 Tramadol acts centrally as a weak μ-opioid receptor agonist. It inhibits ascending pain pathways.9,13 The liver demethylates tramadol to the active metabolite O-desmethyltramadol (M1), which is a μ-opioid receptor agonist.9 The cytochrome P450 pathways, particularly the CYP2D6 enzymes, are the primary actors in this process.9 The M1 metabolite’s affinity for the μ-opiate receptors in the central nervous system (CNS) may be as great as 700 times that of the parent drug.9

In addition to tramadol’s effect on μ-opioid receptors, tramadol differs from other short-acting opioids through its action on the CNS. Tramadol blocks the reuptake of serotonin and norepinephrine, two neurotransmitters directly involved in the inhibitory pain pathway.9,11 Norepinephrine and serotonin modulation differentiate tramadol from classic opioids.9,14 Tramadol can cause unwanted AEs such as sedation, euphoria, and respiratory depression. However, since tramadol’s affinity for μ-opioid receptors is relatively low compared to other opioids, the incidence of unwanted AEs is comparatively low when used appropriately.15

Indications and Uses

Tramadol is indicated for the management of moderate to severe pain in adults who require an opioid analgesic.4 This includes its use for perioperative pain relief and the treatment of chronic pain, including chronic cancer pain.4,16 In cases of persistent postoperative pain relief, tramadol may be co-administered with a non-opioid analgesic (e.g., acetaminophen).17 Tramadol has also been used to manage pain from chronic, non-cancer conditions such as osteoarthritis, rheumatoid arthritis, musculoskeletal injuries, and chronic back pain;17,18 however, long-term use of the drug to treat these conditions is poorly understood.4

Immediate release (IR) tramadol has been used as a first-line treatment for musculoskeletal pain, relief from persistent postoperative pain, and other chronic pain conditions.4,17 However, some medical scientists and clinicians do not recommend the IR formulations as a first-line treatment for chronic, non-cancer pain. They maintain that any potential benefit of tramadol appears to be offset by the risk of misuse and dependence.4,9 If a medical condition does require long-term treatment for pain, prescribers can employ an extended-release (ER) form of the drug.18,19

Tramadol is also used off-label to treat refractory restless legs syndrome and premature ejaculation.9 Medical scientists are evaluating the use of this drug to treat depression and fibromyalgia.20 Some evidence also supports tramadol’s efficacy as a treatment for opioid withdrawal.21

Formulations and Dosing

Tramadol is available in IR and ER formulations and is also manufactured as a combination pill with acetaminophen. Available formulations and strengths of tramadol include the following:22-26

Immediate-release (IR): 50 mg

Extended-release tablet (ER): 100 mg

Extended-release capsule: 100 mg, 150 mg, 200 mg, and 300 mg

Oral suspension: 5 mg/mL

Tramadol/acetaminophen tablets: 37.5 mg/325 mg, respectively. Note that the maximum daily limit of acetaminophen is 4,000 mg per day for healthy adults.27

Immediate-release tramadol is recommended to treat pain for a few days at the lowest effective dose.22,28-30 Immediate-release formulations may be prescribed at 50-100 mg every 4-6 hours for around-the-clock administration. Because it is for moderate to severe pain, tramadol should not be used as an as-needed medication.22 Dose should be individualized through shared decision-making.

For pain lasting more than a few days, ER tramadol is preferred. ER tramadol’s indication is for pain control requiring 24-hour coverage or for an extended period.23 Prescribers can start the ER medication at 100 mg daily, increasing by 100 mg every five days until the maximum daily dosage of 300 mg is reached.23 If, however, the patient has been taking the IR formulation, before prescribing the ER form, the prescriber should calculate the patient’s existing 24-hour dose. The prescriber should start ER tramadol at a dose rounded down to the next lowest 100 mg increment, increasing as needed while considering safety, comorbidities, and other factors.23 The effective therapeutic serum concentration of tramadol is 0.1 to 0.3 mg/L.23

As with other medications, prescribers should employ the lowest effective dose for the shortest effective duration.22,29 Treatment with tramadol should not be abruptly discontinued.22,29

Tramadol Safety Considerations

Adverse Effects of Tramadol

In clinical trials, tramadol’s most frequently reported treatment-emergent AEs (occurring in at least 15% of patients) included dizziness/vertigo, nausea, constipation, headache, somnolence, vomiting, and pruritus, many of which occurred early in treatment and were often dose-related.22,29 Over time, cumulative incidence increased with continued exposure; by 90 days of treatment, approximately 40% of patients experienced nausea, 46% constipation, 33% dizziness, 32% headache, and 25% somnolence, with vomiting and pruritus reported in up to 17% and 11% of patients, respectively.22,29

Other bothersome but less frequent effects (experienced by fewer than 5% of patients) include sweating, dry mouth, dyspepsia, diarrhea, nervousness, and sleep disturbance.22,29 Most reactions were mild to moderate in severity, although AEs were a common reason for discontinuation in clinical studies, underscoring the importance of individualized titration and ongoing tolerability assessment.19

Because μ-opioid receptors are distributed throughout the central nervous system and the gastrointestinal (GI) tract, opioid analgesics can affect GI function.30,31 Tramadol’s activity at opioid receptors, along with its additional serotonergic and noradrenergic effects, can contribute to GI AEs such as nausea, vomiting, abdominal cramping, and constipation.4 Although tramadol appears to interfere with GI motility to a lesser extent than some other opioids, clinically meaningful GI effects can still occur.28 The incidence may be higher than with some other opioids.4 These effects may relate to tramadol’s unique dopaminergic and serotonergic activity and may be dose-related.4 Slow titration and gradual dose escalation may help improve tolerability.

Constipation remains a particularly important concern with chronic opioid therapy, especially in older adults.4 Opioid-induced constipation often persists over time and typically requires ongoing management, commonly with stimulant laxatives, for the duration of therapy. Tramadol may be less constipating than some stronger opioids, but the risk is still present.4 Opioid stimulation of gut receptors reduces peristalsis, slows intestinal transit, and increases fluid reabsorption, mechanisms that can worsen or precipitate bowel motility problems. These effects are especially concerning in patients with known or suspected GI obstruction, and opioids themselves may contribute to complications such as paralytic ileus, which is often seen in postoperative settings.22,31

Boxed Warnings and Contraindications

Tramadol has been associated with multiple AEs, and in some cases, these can cause serious morbidities and death.32 Tramadol has a boxed warning highlighting multiple serious safety risks that require careful prescribing and monitoring.22-26 The drug exposes patients to the dangers of addiction, abuse, and misuse, which can lead to overdose and death, and therefore is subject to the FDA’s Opioid Analgesic REMS program to ensure prescribers counsel patients appropriately.22-26,33

The REMs program has been updated.33 Beginning March 31, 2025, pharmacies and other dispensers of opioid analgesics (OAs) may begin ordering mail-back envelopes (MBEs) to provide to patients.33 This REMS modification includes the option to order MBEs from OA REMS manufacturers but does not require them to stop providing other disposal options. OA manufacturers have developed a Patient Education Sheet for patients on safe disposal of opioid analgesics, which is included with each MBE, and an updated Patient Guide for health care providers to counsel patients on options for safe disposal of unused opioid analgesics.33

Tramadol boxed warning emphasizes the risk of serious, life-threatening, or fatal respiratory depression, particularly during treatment initiation or dose escalation.22-26 This risk is especially pronounced in children who are “ultra-rapid metabolizers,” a phenomenon that may be caused by a cytochrome P450 enzyme polymorphism. This can increase the production of tramadol’s active metabolites, which can lead to oversedation, respiratory depression, and death.22,23,25,26 In 2015, the FDA issued a warning for the use of tramadol in children who were ultra-rapid metabolizers based on documented cases confirming this adverse event.34 In 2017, the agency updated the warning, making it contraindicated in patients under the age of 12 and in children with obesity, obstructive sleep apnea (OSA), or severe lung disease.35 Tramadol’s use is also contraindicated after tonsillectomy or adenoidectomy in pediatric patients younger than 18 years old.36 As a result, prescribers are advised to carefully evaluate adolescents for risk factors such as obesity, OSA, severe pulmonary disease, or postoperative airway compromise before considering tramadol use.37

The boxed warning further cautions that drug interactions involving CYP3A4 and CYP2D6 inhibitors or inducers can alter tramadol or metabolite levels in ways that increase toxicity or reduce efficacy.22,23,25,26 Concomitant use of tramadol and drugs that induce or inhibit cytochrome P450 enzymes—including 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors—or sudden discontinuation of these drugs, may cause harmful drug-drug interactions. Use of tramadol with other drugs that cause CNS depression, like alcohol and benzodiazepines, can cause coma, respiratory depression, sedation, and death.22,23,25,26 Moreover, prolonged use of tramadol during pregnancy can lead to symptoms of withdrawal in neonates.22,23,25,26

Tramadol’s boxed warning also advises that accidental ingestion of tramadol can cause an overdose, and an overdose may be fatal. Life-threatening respiratory depression and death have been documented with tramadol.

Contraindications to tramadol use include the following:22,23,25,26

Children younger than 12 years of age

Postoperative use in children younger than 18 years following tonsillectomy and/or adenoidectomy

Significant respiratory depression

Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment

Known or suspected GI obstruction, including paralytic ileus

Hypersensitivity to tramadol, any other component of the product, or opioids

Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the past 14 days

Additional Warnings and Clinical Considerations

Anaphylactoid and Hypersensitivity Reactions

Anaphylaxis caused by tramadol appears to be rare; the prescribing information notes that anaphylactoid reactions were reported as an adverse event in less than 1% of post-marketing studies and/or case reports about tramadol.22,23,25,26

Respiratory and Pulmonary Considerations

Opioids cause respiratory depression by decreasing the sensitivity of the central chemoreceptors to carbon dioxide (CO2) and by depressing the ventilatory response to hypoxia. However, respiratory depression is generally preventable with appropriate dosing and monitoring.38

Tramadol can cause respiratory depression and CO2 retention, so it should be used cautiously in patients who have chronic obstructive pulmonary disease (COPD), cor pulmonale (right-sided heart failure caused by lung problems), decreased respiratory reserve, hypoxia, hypercapnia, or respiratory depression.22,23,25,26 Adverse respiratory effects are more likely to occur when therapy with tramadol is started or when the dose is increased.

Although some studies suggest tramadol may be less likely than other opioids to cause respiratory depression, evidence is limited,39 and the prescribing information emphasizes that tramadol may cause serious and life-threatening respiratory depression.22,23,25,26

Neurologic Effects

Tramadol can cause CNS depression through CO2 retention, which may affect patient safety, especially in individuals with impaired consciousness.40 Overdose studies have demonstrated frequent CNS depression, nausea/vomiting, tachycardia, and seizures, often resolving with supportive care but sometimes requiring naloxone administration.40

Seizures are a well-documented AE.22,23,25,26 While prescribing information reports less than 1% incidence in postmarketing data, risk increases in patients with pre-existing seizure disorders or concomitant use of medications or conditions that lower seizure threshold (e.g., some antipsychotics and antidepressants, muscle relaxers, other opioids).22,23,25,26 Seizure risk may also increase due to alcohol withdrawal, CNS infection, head trauma, malignancy, or metabolic disorders.22,23,25,26 Seizures most often occur with overdose or misuse, though they may also occur with therapeutic dosing in high-risk situations.22,23,25,26

Serotonin syndrome is a potentially fatal condition that is caused by the accumulation of serotonin (5-HT) at CNS receptors.15,41 Patients with slower rates of CYP2D6 function and those with deficient 5-HT uptake are at risk for serotonin syndrome when taking tramadol.15,41 Symptoms typically occur within 24 hours of exposure, dose change, or change in CYP2D6 inhibitor use.15,41

Tramadol use in patients undergoing cranial surgery or with head trauma also warrants careful consideration. Opioid analgesics are commonly used post-craniotomy, but they may increase intracranial pressure and interfere with neurologic assessment, potentially contributing to oversedation, respiratory depression, nausea, and vomiting.42,43 Its analgesic effectiveness in the craniotomy setting is generally considered lower than that of morphine.43 Importantly, seizures represent a particular concern in patients with head injury or stroke, as tramadol-related seizure risk appears to be higher in these populations.43 These factors should be carefully weighed when considering tramadol for pain management in patients with head trauma or following craniotomy.

Endocrine and Metabolic Effects

Extended opioid use has been associated with endocrine disturbances, including secondary hypogonadism, which may contribute to infertility, mood disorders, osteoporosis, and sexual dysfunction.44,45

A small study of 25 men dependent on tramadol found statistically significant associations between duration and dose of tramadol use and reductions in serum testosterone levels.46 Lower testosterone levels also correlated with higher addiction severity scores, suggesting potential suppression of the hypothalamic-pituitary-gonadal axis and clinically relevant testosterone deficiency in this population.46

Hypoglycemia is another rare but clinically important adverse effect reported with tramadol, most commonly within the first few weeks of therapy and occasionally requiring hospitalization.47-49 Based on retrospective review and case-control analysis, hypoglycemia risk appears greatest in older adults and individuals with predisposing metabolic factors.49 Primary care physicians and other members of the healthcare team should remain alert to this possible etiology of otherwise unexplained hypoglycemia, especially shortly after tramadol initiation.48 Proposed mechanisms include potential serotonergic effects on glucose regulation, although the exact pathway remains unclear.47 Hypoglycemia has also been reported in tramadol overdose settings.49

Tramadol should be used cautiously in patients with thyroid dysfunction, particularly hypothyroidism, in whom opioid clearance may be reduced.50,51 Additional caution is warranted in individuals with severe obesity (BMI 40 kg/m² or greater), as comorbidities commonly associated with obesity—such as OSA, diabetes, COPD, and other pulmonary conditions—may increase tramadol-related risk or exacerbate underlying disease.22,23,25,26

Cardiac Adverse Effects

In therapeutic doses, clinically significant cardiovascular adverse effects appear uncommon with tramadol.52 However, tramadol may contribute to hypotension or orthostatic hypotension, particularly in older adults, and episodes of syncope have been reported.52

Very rare case reports have described possible tramadol-associated pericarditis. For example, an 88-year-old patient developed acute pericarditis shortly after starting tramadol, with symptom resolution after discontinuation.53 Although pericarditis has been listed as a potential adverse effect in pharmacology literature, it is generally characterized as rare and typically mild, and causality remains difficult to confirm given multiple potential contributing factors.54

Tramadol has also been associated with QTc interval prolongation in some reports, potentially related to potassium channel blockade.52 In a 2016 analysis involving 1,270 patients receiving tramadol in acute care settings, QT prolongation was observed following administration.55 Routine electrocardiogram monitoring is not universally required; however, healthcare professionals may consider periodic QT assessment in patients with known cardiovascular disease, concurrent QT-prolonging medications, electrolyte abnormalities, or other risk factors.52,55

Mental Health

Patients with chronic pain and coexisting mental health conditions, including depression or anxiety, should receive tramadol only with appropriate monitoring due to increased vulnerability to opioid misuse, opioid use disorder, or intentional overdose. Tramadol should not be prescribed to patients who are actively suicidal.56 Caution is also warranted in individuals with toxic (substance-induced) psychosis, as tramadol’s CNS effects—such as confusion, drowsiness, and insomnia—may exacerbate psychiatric instability. Psychosis has been rarely reported with tramadol use.67,58

Urologic Effects

Opioids, including tramadol, may worsen lower urinary tract symptoms and should be used cautiously in patients with conditions such as benign prostatic hyperplasia, urethral stricture, or urinary retention.59-61 Opioid receptor stimulation can inhibit normal bladder function and micturition, and both urinary retention and urinary incontinence have been reported as AEs of tramadol.60-63

Tramadol Use in Special Populations

For certain patient groups—including pediatric patients, older adults, patients with renal or hepatic impairment, and individuals who are pregnant or breastfeeding—tramadol use and dosing should be evaluated and prescribed cautiously.22,23,25,26

Pediatrics

Tramadol is contraindicated in children younger than 12 years of age and in adolescents younger than 18 years following tonsillectomy or adenoidectomy due to the risk of serious, life-threatening respiratory depression.22,23,25,26 Use should also be avoided in children with obesity, OSA, or severe pulmonary disease, and particular caution is warranted because ultra-rapid CYP2D6 metabolizers are at increased risk of oversedation, respiratory depression, and death.22,23,25,26

Older Adults

Tramadol may offer pain relief in selected older patients but should be used cautiously and with careful monitoring.14,19 The 2019 American Geriatrics Society (AGS) revised the AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults.64 The updated criteria advised cautious use of tramadol in older adults, partly due to CNS adverse effects and partly due to emerging safety concerns.14,64 In addition, in patients with creatinine clearance (CrCl) less than 30 mL/min, IR tramadol should be reduced, and ER formulations should be avoided entirely.64

The 2023 Beers Criteria includes a warning to use tramadol with caution. It is associated with hyponatremia (abnormally low sodium in the blood) and syndrome of inappropriate antidiuretic hormone secretion (SIADH).65 SIADH occurs when the pituitary gland secretes excessive antidiuretic hormone, leading to water retention and low sodium levels.66 This syndrome has symptoms similar to hyponatremia: CNS dysfunction due to plasma osmolality less than 240 mOsm/kg (or mmol/kg), which can lead to confusion or other cognitive disorders.66

This reinforces that hyponatremia with tramadol is a clinically meaningful consideration in geriatric prescribing.67

Older adults are more prone to CNS effects from tramadol, including dizziness, orthostatic hypotension, and somnolence4,19,68 which contribute to falls and fall-related injuries in this population.68 The risk appears to be highest soon after therapy initiation, declining somewhat over time.69

Evidence evaluating comparative fall and injury risk has been mixed. One analysis in older adults with osteoarthritis found that injury rates from tramadol-associated falls were similar to those observed with other opioids.70 Additional population-level data, including nearly 2 million patients suggests a potential association between tramadol use and increased hip fracture risk compared with codeine. Patients taking tramadol were 1.3 times more likely to incur a hip fracture, with men younger than 65 at greatest risk.71

Pharmacokinetic differences in older adults further support cautious prescribing. The volume of distribution for ER tramadol may be higher in elderly patients, while renal clearance and elimination rates may be lower.72 In practice, dosing should begin at the lower end of the recommended range, with slow titration and close monitoring. Extended-release formulations should generally be avoided in older adults and, if used, should be prescribed only at the lowest effective dose with extreme caution. These strategies reflect standard geriatric principles of “start low and go slow” to minimize AEs and optimize tolerability.14,73

Hepatic or Renal Impairment

Tramadol’s clearance is reduced in hepatic insufficiency, increasing systemic exposure.9,74 In cirrhosis, the bioavailability and elimination half-life of tramadol may be prolonged due to decreased hepatic clearance. For this reason, experts generally recommend extending dosing intervals in patients with hepatic impairment to avoid accumulation and toxicity.4

Because tramadol and its metabolites are primarily eliminated by the kidneys, renal function must be evaluated prior to prescribing. For patients with severe renal impairment (CrCl less than 30 mL/min), tramadol should generally be avoided due to prolonged elimination and increased risk of drug accumulation and AEs.4 Tramadol is contraindicated in this population.4 However, if tramadol is considered necessary and the potential benefits outweigh the risks, IR tramadol may be used cautiously with dose adjustment. Typical recommendations are to start at 50 mg and limit total daily dosing to no more than 200 mg/day in patients with CrCl 10-30 mL/min, and no more than 100 mg/day in those with CrCl less than 10 mL/min or receiving dialysis.4 These adjustments reflect slowed clearance and are intended to reduce accumulation risk. If a patient has hepatic impairment and an opioid analgesic is also indicated, immediate-release tramadol appears safe if started at a low dose and titrated slowly.22

Pregnancy and Breastfeeding

Published data on tramadol use in pregnancy are limited; however, some studies have suggested possible associations between opioid exposure (including tramadol) and congenital malformations, cardiovascular defects, and clubfoot.75 Prolonged opioid use during pregnancy may also result in neonatal abstinence syndrome (NAS)—opioid withdrawal in the newborn that typically occurs in the immediate postnatal period—which can be serious and potentially life-threatening.76-78 As a lipophilic opioid, tramadol readily crosses the placenta.76-78 Reported prevalence rates of NAS among newborns exposed to opioids (prescribed or illicit) during pregnancy have ranged from approximately 55% to 94%.79

Although neonatal opioid withdrawal is rarely life-threatening, it may be associated with complications such as weight loss, fever, and seizures.77 Additional concerns reported with prenatal opioid exposure include spontaneous abortion, premature rupture of membranes, preeclampsia, placental abruption, and fetal demise.75 Neonatal abstinence syndrome is also linked to longer hospitalizations and increased healthcare costs, and long-term neurodevelopmental and behavioral impacts remain an area of concern.76,78

Consistent with national recommendations, healthcare providers should screen pregnant patients for substance use disorders at the first prenatal visit. The American College of Obstetricians and Gynecologists (ACOG) supports universal screening to reduce missed diagnoses, recognizing that many pregnant individuals with substance use disorders may not present with obvious risk indicators.80 Primary care physicians and other members of the healthcare team should consult the PLLR guidance when evaluating tramadol use in pregnancy.

Regarding breastfeeding, the FDA issued a 2017 Drug Safety Communication advising that tramadol should not be used during breastfeeding.81 A literature review did not identify documented AEs in infants exposed specifically to tramadol through breast milk. However, tramadol and its active metabolite are known to be present in breast milk, and tramadol carries similar risks to codeine in the setting of ultra-rapid CYP2D6 metabolism, which has been linked to serious infant respiratory depression and death with codeine exposure.81

Tramadol Misuse and Overdose

Tramadol Use Disorder

The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria for the diagnosis of opioid use disorder state that opioid use disorder is present if opioid use is causing significant impairment and if two of 11 specific behaviors are present within a 12-month period.82 Those behaviors include tolerance, withdrawal, and taking the opioid in larger amounts or over a longer period than was intended.82 Published information about tramadol use disorder is less extensive than that for other opioids, and the incidence of tramadol misuse is unknown, but clinical experience confirms that tramadol misuse is not unusual, and it can evolve to opioid use disorder over time.2,11,83

Tramadol Overdose

Patients who overdose on tramadol may develop both opioid-related and tramadol-specific AEs. Reported symptoms include nausea and vomiting, hypertension, tachycardia, CNS depression, respiratory depression, agitation, and seizures.38,84,85 Tramadol overdose differs from other opioids in two important ways: 1) serotonin syndrome may occur, and 2) seizures are relatively common.4,9,84,85 Seizures appear to be related to tramadol’s pharmacologic properties rather than secondary complications (e.g., hypoxemia) that can occur with opioid poisoning.84,85

Rare cases of cardiogenic shock have also been described following tramadol overdose.86,87 Death due to tramadol alone appears uncommon; fatalities more often involve co-ingestants. The toxic dose is not well established.85 Intentional ingestion for self-harm and pediatric exploratory ingestion represent the most frequent clinical contexts in which significant toxicity occurs.85

Patients who overdose with self-harm intent, as well as children with non-trivial ingestions, should be referred to a hospital. Symptomatic patients should be admitted.19 Supportive care is the primary management strategy for CNS, cardiovascular, and respiratory complications.19

Naloxone is effective in reversing opioid-induced hypoventilation and has generally been used safely in tramadol overdose. However, the literature remains mixed regarding whether naloxone may precipitate or increase seizure frequency in this setting.88,89 Primary care physicians and other members of the healthcare team must weigh naloxone’s benefits (restoring ventilation) against potential risks, including possible seizure induction and precipitated withdrawal in patients experiencing tramadol overdose.

Patient Case

A 50-year-old woman presenting with osteoarthritis and chronic low back pain visits the clinic, presenting with worsening pain over the past 3 months that now interferes with sleep and mobility despite scheduled alternating of acetaminophen and naproxen tablets and topical NSAID. She has a history of hypertension and a BMI of 30. Additional current medications include lisinopril, hydrochlorothiazide, and sertraline.

What medication alternative might be considered?

Her primary care clinician considers starting tramadol for moderate to severe pain that has not responded to non-opioid measures.

What are some considerations before prescribing?

Determine liver function and renal function. Determine whether to prescribe an immediate-release or extended-release formulation. During the visit, the clinician must decide whether tramadol is appropriate given her age, fall risk, SIADH/hyponatremia risk with concomitant sertraline, and if used, how to individualize the dose, avoid ER tramadol. The patient should be asked when her last menstrual cycle occurred to determine menopause status and ensure no risk of pregnancy. Determine next follow-up appointment to monitor sodium and respiratory status, and counsel on boxed warnings, drug interactions, and safe storage and disposal under the updated opioid REMS program.

Summary

Tramadol is a centrally acting synthetic opioid analgesic used for short- and long-term pain management in adults. Available in both IR and ER formulations, its analgesic effect is mediated by μ-opioid receptor activity and inhibition of norepinephrine and serotonin reuptake—features that distinguish it from traditional opioids. Although classified as a Schedule IV controlled substance, tramadol can still be misused and carries a meaningful risk of opioid use disorder, particularly with prolonged therapy.

Cautious use is warranted in older adults, patients with renal or hepatic impairment, and those with psychiatric conditions or substance use risk. Prescribing in pediatric patients and during pregnancy or breastfeeding carries specific safety concerns and should generally be avoided. Tramadol shares many class adverse effects with other opioids, but healthcare professionals must also consider tramadol-specific risks such as seizures, serotonin syndrome, and potential hyponatremia in older adults. When used thoughtfully, tramadol can be an effective component of pain management; however, its risks should not be underestimated, and careful patient selection, dosing, and monitoring are essential.

References

Etemadi A, Poustchi H, Calafat AM, et al. Opiate and Tobacco Use and Exposure to Carcinogens and Toxicants in the Golestan Cohort Study. Cancer Epidemiol Biomarkers Prev. 2020;29(3):650-658. doi:10.1158/1055-9965.EPI-19-1212

Degenhardt L, Grebely J, Stone J, et al. Global patterns of opioid use and dependence: harms to populations, interventions, and future action. Lancet. 2019;394(10208):1560-1579. doi:10.1016/S0140-6736(19)32229-9

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Tramadol. [Updated 2020 Nov 24]. Accessed January 9, 2026. https://www.ncbi.nlm.nih.gov/books/NBK548235/

Roulet L, Rollason V, Desmeules J, Piguet V. Tapentadol Versus Tramadol: A Narrative and Comparative Review of Their Pharmacological, Efficacy and Safety Profiles in Adult Patients. Drugs. 2021;81(11):1257-1272. doi:10.1007/s40265-021-01515-z

Drug Enforcement Administration, Diversion Control Division. Tramadol. 2020. https://www.deadiversion.usdoj.gov/drug_chem_info/tramadol.pdf

Drug Enforcement Administration, Diversion Control Division. Controlled Substance Schedules. July 2021. Retrieved from https://www.deadiversion.usdoj.gov/schedules/

Health Canada. Regulations Amending the Narcotic Control Regulations (Tramadol): SOR/2021-43. Health Canada. March 31, 2021. Accessed January 9, 2026. https://gazette.gc.ca/rp-pr/p2/2021/2021-03-31/html/sor-dors43-eng.html

Krebs EE, Gravely A, Nugent S, et al. Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The SPACE Randomized Clinical Trial. JAMA. 2018;319(9):872-882. doi:10.1001/jama.2018.0899

Thiels CA, Habermann EB, Hooten WM, Jeffery MM. Chronic use of tramadol after acute pain episode: cohort study. BMJ. 2019;365:l1849. Published 2019 May 14. doi:10.1136/bmj.l1849

Power I. An update on analgesics. Br J Anaesth. 2011;107(1):19-24. doi:10.1093/bja/aer126

Balhara YPS, Parmar A, Sarkar S. Use of Tramadol for Management of Opioid Use Disorders: Rationale and Recommendations. J Neurosci Rural Pract. 2018;9(3):397-403. doi:10.4103/jnrp.jnrp_42_18

World Health Organization. Tramadol Update Review Report. Expert Committee on Drug Dependence Thirty‐sixth Meeting Geneva. 2014; 16‐20.

Lee J, Yoo HD, Bae JW, Lee S, Shin KH. Population pharmacokinetic analysis of tramadol and O-desmethyltramadol with genetic polymorphism of CYP2D6. Drug Des Devel Ther. 2019;13:1751-1761. Published 2019 May 23. doi:10.2147/DDDT.S199574

Yang BR, Um HY, Lee MT, Kim MS, Jung SY. Characterizing tramadol users with potentially inappropriate co-medications: A latent class analysis among older adults. PLoS One. 2021;16(2):e0246426. Published 2021 Feb 19. doi:10.1371/journal.pone.0246426

Beakley BD, Kaye AM, Kaye AD. Tramadol, pharmacology, side effects, and serotonin syndrome: A review. Pain Physician. 2015;18(4):395-400.

Besic N, Smrekar J, Strazisar B. Acute pain and side effects after tramadol in breast cancer patients: results of a prospective double-blind randomized study. Sci Rep. 2020;10(1):18766. Published 2020 Oct 30. doi:10.1038/s41598-020-75961-2

Lee JH, Kim JH, Kim JH, et al. Efficacy and Safety of Transdermal Buprenorphine versus Oral Tramadol/Acetaminophen in Patients with Persistent Postoperative Pain after Spinal Surgery. Pain Res Manag. 2017;2017:2071494. doi:10.1155/2017/2071494

Kizilbash A, NgĂ´-Minh CT. Review of extended-release formulations of Tramadol for the management of chronic non-cancer pain: focus on marketed formulations. J Pain Res. 2014;7:149-161. Published 2014 Mar 24. doi:10.2147/JPR.S49502

Angeletti C, Guetti C, Paladini A, Varrassi G. Tramadol Extended-Release for the Management of Pain due to Osteoarthritis. ISRN Pain. 2013;2013:245346. Published 2013 Sep 4. doi:10.1155/2013/24534

Koncz S, Papp N, Menczelesz N, Pothorszki D, Bagdy G. EEG and Sleep Effects of Tramadol Suggest Potential Antidepressant Effects with Different Mechanisms of Action. Pharmaceuticals (Basel). 2021;14(5):431. Published 2021 May 4. doi:10.3390/ph14050431

Shah K, Stout B, Caskey H. Tramadol for the Management of Opioid Withdrawal: A Systematic Review of Randomized Clinical Trials. Cureus. 2020;12(7):e9128. Published 2020 Jul 11. doi:10.7759/cureus.9128

TRAMADOL HYDROCHLORIDE tablet. Prescribing Information. ACI Healthcare USA, Inc. Updated December 14, 2023. Accessed December 29, 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f3c7d874-8f9e-4687-9dac-2356ecfa86f9

TRAMADOL HYDROCHLORIDE tablet, film coated TRAMADOL HYDROCHLORIDE ER- tramadol hydrochloride tablet, extended release. Prescribing Information. Abbreviated New Drug Application. Updated June 6, 2023. Accessed December 29, 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c34a95e3-d508-428f-9022-19cc5a90b4ec

TRAMADOL HYDROCHLORIDE capsule, extended release. Prescribing Information. H.J. Harkins Company, Inc. Updated October 19, 2012. Accessed December 29, 2025. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e3476daa-2b3c-455e-b5c4-3c011e03315b

TRAMADOL HYDROCHLORIDE solution. Palmetto Pharmaceuticals, Inc. December 9, 2024. Accessed January 23, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2804c640-9d47-4b40-b58b-da321b79cf39

TRAMADOL HYDROCHLORIDE AND ACETAMINOPHEN- tramadol hydrochloride and acetaminophen tablet, film coated. Prescribing Information. Abbreviated New Drug Application. Updated December 22, 2025. Accessed January 23, 2026. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ab84058e-e52c-4b81-badc-4b0c26aab259#section-2

Food and Drug Administration. For Consumers. Consumer Updates. Don’t Overuse Acetaminophen. FDA. February 1, 2024. Accessed January 26, 2026. https://www.fda.gov/consumers/consumer-updates/dont-overuse-acetaminophen

Amaechi O, Huffman MM, Featherstone K. Pharmacologic Therapy for Acute Pain. Am Fam Physician. 2021 Jul 1;104(1):63-72

Kim HC, Yoon DY, Lee S, Jang IJ, Hong JH, Kim J. Comparative pharmacokinetics between two tablets of tramadol 37.5 mg/acetaminophen 325 mg and one tablet of tramadol 75 mg/acetaminophen 650 mg for extended-release fixed-dose combination. Transl Clin Pharmacol. 2022;30(2):112-119. doi:10.12793/tcp.2022.30.e12

Yamanaka T, Sadikot RT. Opioid effect on lungs. Respirology. 2013;18(2):255-262. doi:10.1111/j.1440-1843.2012.02307.x

Camilleri M, Lembo A, Katzka DA. Opioids in Gastroenterology: Treating Adverse Effects and Creating Therapeutic Benefits. Clin Gastroenterol Hepatol. 2017;15(9):1338-1349. doi:10.1016/j.cgh.2017.05.014

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

Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS). FDA. March 31, 2025. Accessed January 26, 2026. https://www.fda.gov/drugs/information-drug-class/opioid-analgesic-risk-evaluation-and-mitigation-strategy-rems

FDA Drug Safety Communication: FDA evaluating the risks of using the pain medicine tramadol in children aged 17 and younger, September 21, 2015. Accessed December 2, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-evaluating-risks-using-pain-medicine-tramadol-children-aged-17-and

U.S. Food and Drug Administration. FDA Drug Safety Podcast: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. FDA. Updated 01/14/2022. https://www.fda.gov/drugs/fda-drug-safety-podcasts/fda-drug-safety-podcast-fda-restricts-use-prescription-codeine-pain-and-cough-medicines-and-tramadol

Renny MH, Jent V, Townsend T, CerdĂĄ M. Impact of the 2017 FDA Drug Safety Communication on Codeine and Tramadol Dispensing to Children. Pediatrics. 2022;150(5):e2021055887. doi:10.1542/peds.2021-055887

Cravero JP, Agarwal R, Berde C, et al. The Society for Pediatric Anesthesia recommendations for the use of opioids in children during the perioperative period. Paediatr Anaesth. 2019;29(6):547-571. doi:10.1111/pan.13639

Baldo BA. Opioid-induced respiratory depression: clinical aspects and pathophysiology of the respiratory network effects. Am J Physiol Lung Cell Mol Physiol. 2025;328(2):L267-L289. doi:10.1152/ajplung.00314.2024

Edinoff AN, Kaplan LA, Khan S, et al. Full Opioid Agonists and Tramadol: Pharmacological and Clinical Considerations. Anesth Pain Med. 2021;11(4):e119156. Published 2021 Sep 6. doi:10.5812/aapm.119156

Manouchehri A, Nekoukar Z, Malakian A, Zakariaei Z. Tramadol poisoning and its management and complications: a scoping review. Ann Med Surg (Lond). 2023;85(8):3982-3989. Published 2023 Jul 7. doi:10.1097/MS9.0000000000001075

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.2018.04.025

Kvolik S, Koruga N, Skiljic S. Analgesia in the Neurosurgical Intensive Care Unit. Front Neurol. 2022;12:819613. Published 2022 Jan 25. doi:10.3389/fneur.2021.819613

Haldar R, Kaushal A, Gupta D, Srivastava S, Singh PK. Pain following craniotomy: reassessment of the available options. Biomed Res Int. 2015;2015:509164. doi:10.1155/2015/509164

Merdin A, Merdin FA, Gündüz Ş, Bozcuk H, Coşkun HŞ. Opioid endocrinopathy: A clinical problem in patients with cancer pain. Exp Ther Med. 2016;11(5):1819-1822. doi:10.3892/etm.2016.3156

de Vries F, Bruin M, Lobatto DJ, et al. Opioids and Their Endocrine Effects: A Systematic Review and Meta-analysis. J Clin Endocrinol Metab. 2020;105(3):1020-1029. doi:10.1210/clinem/dgz022

Darweesh AEM, Khalifa H, Gabra RH. et al. Male Sex Hormone affection in patients with Tramadol dependance. Middle East Curr Psychiatry. 2020;27,21. doi.org/10.1186/s43045-020-00027-y

Bourne C, Gouraud A, Daveluy A, et al. (2013). Tramadol and hypoglycaemia: comparison with other step 2 analgesic drugs. Br J Clin Pharmacol. 2013;75(4):1063-1067.

Pratiwi C, Mokoagow MI, Made Kshanti IA, Soewondo P. The risk factors of inpatient hypoglycemia: A systematic review. Heliyon. 2020;6(5):e03913. Published 2020 May 11. doi:10.1016/j.heliyon.2020.e03913

Fournier JP, Azoulay L, Yin H, Montastruc JL, Suissa S. (2015). Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med. 2015;175(2):186-193.

Surks MI, Ortiz E, Daniels GH, et al. Subclinical Thyroid Disease: Scientific Review and Guidelines for Diagnosis and Management. JAMA. 2004;291(2):228–238. doi:10.1001/jama.291.2.228

Pezeshki B, Pourmontaseri H, Homayounfar R, Moghaddam MT, Dehghan A. Thyroid function and opium use disorder: a cross-sectional study on the Fasa adults cohort study (FACS), 2017. BMC Endocr Disord. 2023;23(1):264. Published 2023 Nov 30. doi:10.1186/s12902-023-01467-3

Behzadi M, Joukar S, Beik A: Opioids and Cardiac Arrhythmia: A Literature Review. Med Princ Pract. 2018;27:401-414. doi: 10.1159/000492616

Krantz MJ, Garcia JA, Mehler PS. Tramadol-associated pericarditis. Int J Cardiol. 2005;99(3):497-498. doi:10.1016/j.ijcard.2004.05.075

Mladěnka P, Applová L, Patočka J, et al. Comprehensive review of cardiovascular toxicity of drugs and related agents. Med Res Rev. 2018;38(4):1332-1403. doi:10.1002/med.21476

Keller GA, Alvarez PA, Ponte ML, et al. Drug-Induced QTc Interval Prolongation: A Multicenter Study to Detect Drugs and Clinical Factors Involved in Every Day Practice. Curr Drug Saf. 2016;11(1):86-98. doi:10.2174/1574886311207040262

Subedi M, Bajaj S, Kumar MS, Yc M. An overview of tramadol and its usage in pain management and future perspective. Biomed Pharmacother. 2019;111:443-451. doi:10.1016/j.biopha.2018.12.085

Chen KJ, Lu ML, Shen WW. Tramadol-related psychosis in a patient with bipolar I disorder. Acta Neuropsychiatr. 2015;27(2):126-128.

Vallersnes OM, Dines AM, Wood DM. Psychosis associated with acute recreational drug toxicity: a European case series. BMC Psychiatry. 2016 Aug 18;16:293. doi: 10.1186/s12888-016-1002-7.

Verhamme KM, Sturkenboom MC, Stricker BH, Bosch R. Drug-induced urinary retention: incidence, management and prevention. Drug Saf. 2008;31(5):373-88. doi: 10.2165/00002018-200831050-00002. PMID: 18422378.

Kahn B, Boazak M, Ragazino J, Sineath RC, Kapral T. An Additive Mix? Acute Urinary Retention in a Patient With Benign Prostatic Hyperplasia Treated With Suboxone, Lurasidone, and Trazodone. Focus (Am Psychiatr Publ). 2018;16(3):292-298. doi:10.1176/appi.focus.20180007

Lofwall MR, Babalonis S, Nuzzo PA, Siegel A, Campbell C, Walsh SL. Efficacy of extended-release tramadol for treatment of prescription opioid withdrawal: a two-phase randomized controlled trial. Drug Alcohol Depend. 2013;133(1):188-197. doi:10.1016/j.drugalcdep.2013.05.010

Meyboom RH, Brodie-Meijer CC, Diemont WL, van Puijenbroek EP. Bladder dysfunction during the use of tramadol. Pharmacoepidemiol Drug Saf. 1999;8 Suppl 1: S63-S6471

Gautam SK, Das PK, Agarwal A. Urinary incontinence induced by tramadol. Indian J Palliat Care. 2013;19(1):76-77. doi:10.4103/0973-1075.110244

By the 2019 American Geriatrics Society Beers CriteriaÂŽ Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers CriteriaÂŽ for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694. doi:10.1111/jgs.15767

By the 2023 American Geriatrics Society Beers CriteriaÂŽ Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers CriteriaÂŽ for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71(7):2052-2081. doi:10.1111/jgs.18372

Mentrasti G, Scortichini L, Torniai M, et al. Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH): Optimal Management. Ther Clin Risk Manag. 2020;16:663-672. Published 2020 Jul 24. doi:10.2147/TCRM.S206066

Daoust R, Paquet J, Moore L, et al. Recent opioid use and fall-related injury among older patients with trauma. CMAJ. 2018;190(16):E500-E506. doi:10.1503/cmaj.171286

Musich S, Wang SS, Schaeffer JA, Slindee L, Kraemer S, Yeh CS. Safety Events Associated with Tramadol Use Among Older Adults with Osteoarthritis. Popul Health Manag. 2021;24(1):122-132. doi:10.1089/pop.2019.0220

Hunnicutt JN, Hume AL, Liu SH, Ulbricht CM, Tjia J, Lapane KL. Commonly Initiated Opioids and Risk of Fracture Hospitalizations in United States Nursing Homes. Drugs Aging. 2018;35(10):925-936. doi:10.1007/s40266-018-0583-x

Janssens WH, Verhoestraete P, Piers RD, Van Den Noortgate NJ. Short-Term Opioid Treatment of Acute Locomotor Pain in Older Adults: Comparison of Effectiveness and Safety between Tramadol and Oxycodone: A Randomized Trial. Geriatrics (Basel). 2024;9(2):46. Published 2024 Apr 5. doi:10.3390/geriatrics9020046

Bahardoust M, Mousavi S, Mozafari JK, et al. Association of tramadol use with risk of hip fractures in patients with osteoarthritis: A systematic review and meta-analysis of observational studies. Int J Orthop Trauma Nurs. 2024;52:101078. doi:10.1016/j.ijotn.2023.101078

Skinner-Robertson S, Fradette C, Bouchard S, Mouksassi MS, Varin F. Pharmacokinetics of tramadol and o-desmethyltramadol enantiomers following administration of extended-release tablets to elderly and young subjects. Drugs Aging. 2015;32(12):1029-1043.

Welsh TP, Yang AE, Makris UE. Musculoskeletal Pain in Older Adults: A Clinical Review. Med Clin North Am. 2020;104(5):855-872. doi:10.1016/j.mcna.2020.05.002

Soleimanpour H, Safari S, Shahsavari Nia K, Sanaie S, Alavian SM. Opioid Drugs in Patients With Liver Disease: A Systematic Review. Hepat Mon. 2016;16(4):e32636. Published 2016 Mar 6. doi:10.5812/hepatmon.32636

Lind JN, Interrante JD, Ailes EC, et al. Maternal Use of Opioids During Pregnancy and Congenital Malformations: A Systematic Review. Pediatrics. 2017;139(6):e20164131. doi:10.1542/peds.2016-4131

Burduli E, Smith CL, Tham P, Shogan M, Johnson RK, McPherson SM. Development and application of a primer and reference assessment tool for neonatal abstinence syndrome: A phase I pilot study. Contemp Clin Trials Commun. 2019;17:100494. Published 2019 Dec 3. doi:10.1016/j.conctc.2019.100494.

Siu A, Robinson CA. Neonatal abstinence syndrome: essentials for the practitioner. J Pediatr Pharmacol Ther. 2014;19(3):147-155. doi:10.5863/1551-6776-19.3.147

Czynski AJ, Davis JM, Dansereau LM, et al. Neurodevelopmental Outcomes of Neonates Randomized to Morphine or Methadone for Treatment of Neonatal Abstinence Syndrome. J Pediatr. 2020;219:146-151.e1. doi:10.1016/j.jpeds.2019.12.018

McQueen K, Murphy-Oikonen J. Neonatal Abstinence Syndrome. N Engl J Med. 2016;375(25):2468-2479. doi:10.1056/NEJMra1600879

Committee Opinion No. 711: Opioid Use and Opioid Use Disorder in Pregnancy. Obstet Gynecol. 2017;130(2):e81-e94. doi:10.1097/AOG.0000000000002235

U.S. Food & Drug Administration. FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. FDA. 4/20/2017. Content current as of: 10/19/2023. Accessed January 9, 2026. https://www.fda.gov/Drugs/DrugSafety/ucm549679.htm

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), American Psychiatric Association, Arlington, VA 2013.

Wang S, Shafique S, Xiao D, Barker K, Wang K, Xie X. Clusters of substance use and mental health variables with emergency room visits in U.S. adults: The 2020 National Survey on Drug Use and Health. J Affect Disord. 2023;339:683-690. doi: 10.1016/j.jad.2023.07.017

Ryan NM, Isbister GK. Tramadol overdose causes seizures and respiratory depression but serotonin toxicity appears unlikely. Clin Toxicol (Phila). 2015;53(6):545-550. doi:10.3109/15563650.2015.1036279

Nakhaee S, Hoyte C, Dart RC, et al. A review on tramadol toxicity: mechanism of action, clinical presentation, and treatment. Forensic Toxicol. 2021;39, 293–310. doi.org/10.1007/s11419-020-00569-0

Belin N, Clairet AL, Chocron S, Capellier G, Piton G. Refractory Cardiogenic Shock During Tramadol Poisoning: A Case Report. Cardiovasc Toxicol. 2017;17(2):219-222. doi:10.1007/s12012-016-9373-z

Perdreau E, Iriart X, Mouton JB, Jalal Z, Thambo JB. Cardiogenic shock due to acute tramadol intoxication. Cardiovasc Toxicol. 2015;15(1):100-103. doi:10.1007/s12012-014-9262-2

Eizadi-Mood N, Ozcan D, Sabzghabaee AM, Mirmoghtadaee P, Hedaiaty M. Does naloxone prevent seizure in tramadol intoxicated patients?. Int J Prev Med. 2014;5(3):302-307.

Lagard C, Malissin I, Indja W, Risède P, Chevillard L, MÊgarbane B. Is naloxone the best antidote to reverse tramadol-induced neuro-respiratory toxicity in overdose? An experimental investigation in the rat. Clin Toxicol (Phila). 2018;56(8):737-743. doi:10.1080/15563650.2017.1401080

DISCLAIMER

The information provided in this course is general in nature, and it is designed solely to provide participants with continuing education credit(s). This course and materials are not meant to substitute for the independent, professional judgment of any participant regarding that participant’s professional practice, including but not limited to patient assessment, diagnosis, treatment, and/or health management. Medical and pharmacy practices, rules, and laws vary from state to state, and this course does not cover the laws of each state; therefore, participants must consult the laws of their state as they relate to their professional practice.

Healthcare professionals must consult their employer, healthcare facility, hospital, or other organization for guidelines, protocols, and procedures to follow. The information provided in this course does not replace those guidelines, protocols, and procedures, but is for academic purposes only, and this course’s limited purpose is for the completion of continuing education credits.

Participants are advised and acknowledge that information related to medications, their administration, dosing, contraindications, adverse reactions, interactions, warnings, precautions, or accepted uses is constantly changing. Any person taking this course understands that such a person must make an independent review of medication information before any patient assessment, diagnosis, treatment and/or health management. Any discussion of off-label use of any medication, device, or procedure is informational only, and such uses are not endorsed hereby.

Nothing contained in this course represents the opinions, views, judgments, or conclusions of RxCe.com LLC. RxCe.com LLC is not liable or responsible to any person for any inaccuracy, error, or omission with respect to this course or course material.

Š RxCe.com LLC 2026: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.

RxCe.com

Š RxCe.com LLC 2025: All rights reserved.

Back to Tramadol: Balancing Pain Relief and Safety in Clinical Practice (Pharmacist, Pharmacy Tech, Physician Assistant, Physician)