Tramadol

Mechanism of Action

Similar to other opioids, tramadol selectively binds to various opiate receptors in the central nervous system (CNS) due to its opioid nature. The liver enzyme CYP2D6 converts tramadol to its active metabolite M1, which has a stronger affinity for the mu receptor than the inactive form. The M1 metabolite demonstrates analgesic potency up to 6 times greater than tramadol. Tramadol does not bind to the mu receptor as much as morphine. Unlike other opioids, tramadol does not reverse its course completely following naloxone administration.[5] The analgesic effect is also attributed to the antinociceptive effect in the descending pathway, secondary to the inhibition of serotonin and norepinephrine reuptake.[6]

Pharmacokinetics

Absorption: The average absolute bioavailability of a 100 mg oral dose is approximately 75%. The average maximum concentration of tramadol and M1 metabolite is observed at 2 and 3 hours, respectively. Steady-state plasma levels of tramadol and M1 metabolite are attained within 2 days with four-times-daily dosing.

Distribution: The volume of distribution of tramadol is 2.6 L/kg in males and 2.9 L/kg in females. The plasma protein binding of tramadol is approximately 20%.

Metabolism: Tramadol is extensively metabolized by CYP2D6 and CYP3A4 enzymes and through conjugation. The primary metabolic pathways involve N- and O-demethylation and glucuronidation or sulfation reactions in the liver. The pharmacologically active metabolite is O-desmethyl-tramadol (M1 metabolite). The formation of M1 metabolite depends on CYP2D6 activity and can be influenced by inhibitory interactions, affecting the therapeutic response. Some individuals are "poor metabolizers" with reduced CYP2D6 activity. CYP2D6 poor metabolizers have increased exposure to tramadol but reduced M1 metabolite formation compared to individuals with normal CYP2D6 activity.[7][8]

Elimination: The elimination of tramadol occurs primarily via renal excretion. About 30% of the administered dose is excreted unchanged in the urine, while approximately 60% is eliminated as metabolites. The remaining fraction is excreted as unidentified or unextractable metabolites.[9]

Administration

Available Dosage Forms and Strengths

Tramadol is available and used in 2 solid formulations—extended release and immediate release. Both the extended-release and immediate-release formulations are available in capsule form. Patients prescribed the extended-release formulation should receive counseling on proper usage, emphasizing that it should not be chewed, crushed, dissolved, or split before administration. Although both formulations are administered regardless of food intake, the extended-release formulation is taken once daily.[10] Tramadol is also available in a liquid formulation as a tramadol hydrochloride solution. The duration for immediate-release tramadol capsules is 1.6 to 1.9 hours.

Dosages

Tramadol is available in various dosages, including 100 mg, 200 mg, and 300 mg for extended release, 50 mg for immediate release, and 5 mg/mL for tramadol solution.

Acute pain: The recommended daily dosage of immediate-release tramadol is 50 mg and 100 mg every 4 to 6 hours. The maximum recommended dosage of tramadol is 400 mg/d.[11]

Chronic non-cancer pain: According to the CDC guidelines, tramadol should be considered only after careful risk-benefit evaluation. Opioids, such as tramadol, are not optimal for chronic non-cancer pain due to limited evidence of efficacy and potential for significant harm.[12] For patients not taking tramadol immediate-release tablets, the treatment with tramadol extended-release should be started at 100 mg once daily. The dosage can be titrated up to 150 mg, 200 mg, and 300 mg every 5 days.[13]

Premature ejaculation (off-label): According to AUA, tramadol is not a first-line therapy. A recent meta-analysis revealed that 25 to 50 mg tramadol on-demand taken before intercourse is effective for premature ejaculation.[3][14][15]

Specific Patient Populations

Hepatic impairment: The recommended dosage of tramadol immediate-release tablets is 50 mg every 12 hours in patients with hepatic impairment. Tramadol extended-release tablets are not recommended in patients with severe hepatic impairment (Child-Pugh Class C).

Renal impairment: In patients with creatinine clearance <30 mL/min, the dosing interval of tramadol immediate-release tablets is every 12 hours, with a maximum daily dosage of 200 mg. Tramadol extended-release should be avoided in patients with <30 mL/min creatinine clearance.

Pregnancy considerations: Tramadol passes through the placental barrier. The American College of Obstetricians and Gynecologists (ACOG) acknowledges the importance of managing pain during pregnancy while maintaining a conservative approach to prescribing opioids. The potential risks to both the pregnant woman and the fetus associated with opioid use during pregnancy should be considered.

Studies have reported associations between opioid use during pregnancy and adverse outcomes such as stillbirth, poor fetal growth, preterm delivery, and neonatal abstinence syndrome.[16] According to ACOG, for postpartum analgesia, the initial step is nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, which reduces the need for opioids. If NSAIDs and acetaminophen are insufficient, low-dose tramadol can be considered.[17]

Breastfeeding considerations: According to the FDA, tramadol is not recommended during breastfeeding. If tramadol is necessary, infants should be closely monitored for signs of sedation, breathing difficulties, and breastfeeding difficulties.[18]

Pediatric patients: Tramadol is contraindicated in children aged 12 or younger. Tramadol is contraindicated for postoperative pain management in patients aged 18 or younger following adenoidectomy or tonsillectomy. Tramadol extended-release formulations are not recommended in pediatric patients.

Older patients: The maximum recommended daily dosage for immediate-release formulation is 300 mg. Tramadol extended-release formulation should be used cautiously.

Adverse Effects

The most common adverse drug reactions with tramadol are nausea, dizziness, pruritus, constipation, vomiting, somnolence, and headache. They tend to occur during the initial treatment rather than the maintenance phase.[19] Tramadol-induced mania has been reported in a patient with no history of bipolar disorder.[20] 

Serious adverse effects include profound sedation and respiratory depression, the latter of which, if severe, may result in death. Adrenal insufficiency requires prompt diagnosis, discontinuation of tramadol, and treatment with steroids.[21] Severe hypotension, syncope, and orthostatic hypotension have also been reported. Tramadol can reduce respiratory drive, leading to CO₂ retention and exacerbating intracranial pressure. Use tramadol cautiously in patients with brain tumors or intracranial pressure.[22] 

Drug-Drug Interactions

CYP2D6 inhibitors: Certain risks are associated with the concomitant use or discontinuation of CYP2D6 inhibitors. Genetic variations of CYP2D6 can affect the severity of the drug. The concomitant use of tramadol and CYP2D6 inhibitors, such as amiodarone, quinidine, fluoxetine, paroxetine, and bupropion, may increase the concentration of tramadol and decrease the concentration of M1 metabolite. As M1 metabolite is a more potent mu-opioid agonist, reduced M1 metabolite exposure could decrease therapeutic effects.

Conversely, increased tramadol can increase the risk of seizures and serotonin syndrome. In addition, after discontinuing a CYP2D6 inhibitor, the tramadol plasma concentration decreases, and the M1 metabolite's plasma concentration increases, which can increase the risk of adverse reactions such as potentially fatal respiratory depression. Therefore, if simultaneous use of a CYP2D6 inhibitor is required, monitor patients closely for adverse reactions, including opioid withdrawal, seizures, and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, clinicians should consider reducing the tramadol dose until therapeutic effects are achieved. Observe patients closely for adverse events, including respiratory depression and sedation.[23]

CYP3A4 inhibitors: The simultaneous use of tramadol and CYP3A4 inhibitors such as erythromycin, ketoconazole, or ritonavir can increase the concentration of tramadol and can result in increased metabolism by CYP2D6 and greater levels of M1 metabolite. Monitor patients for seizures, serotonin syndrome, and fatal respiratory depression. After stopping a CYP3A4 inhibitor, as the effects of the CYP4A4 inhibitor decline, the tramadol concentration decreases, resulting in reduced opioid efficacy or withdrawal symptoms in patients who have developed a physical dependence on tramadol.

If concomitant use is necessary, consider reducing the tramadol dosage until stable drug effects are achieved. Monitor patients closely for seizures, serotonin syndrome, sedation, and respiratory depression. If a CYP3A4 inhibitor is discontinued, consider increasing the tramadol dose until stable therapeutic effects are attained and observe patients for signs and symptoms of opioid withdrawal.

CYP3A4 inducers: The concomitant use of tramadol and CYP3A4 inducers, such as rifampin, phenytoin, or carbamazepine, can decrease the plasma concentration of tramadol, reducing efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. In addition, after discontinuing a CYP3A4 inducer, the tramadol plasma concentration will increase, which could increase adverse reactions such as seizures, serotonin syndrome, or fatal respiratory depression.

If concurrent use is necessary, clinicians should consider escalating the tramadol dose until therapeutic effects are achieved. Patients need to be monitored for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, clinicians should consider reducing the tramadol dose and monitoring for seizures, serotonin syndrome, sedation, and respiratory depression. Patients on carbamazepine, a potent CYP3A4 inducer, may have a decreased analgesic effect of tramadol. Simultaneous administration of tramadol and carbamazepine is not recommended.[24]

Benzodiazepines: Certain risks are associated with the concurrent use of tramadol with benzodiazepines, as combining opioids and benzodiazepines can result in synergistic respiratory depression, significantly raising the likelihood of a drug overdose. Therefore, it is advisable to avoid this combination.[25]

Serotonergic drugs: The simultaneous use of opioids with drugs that affect the serotonergic system has resulted in serotonin syndrome. Examples of drugs include selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, ondansetron, mirtazapine, and trazodone. Patients should be carefully monitored during initiation and dose titration if concurrent use is necessary. Tramadol should be discontinued immediately if serotonin syndrome is suspected.[26]

Monoamine oxidase inhibitors: Interactions of monoamine oxidase (MAO) inhibitors with opioids can lead to serotonin syndrome or opioid toxicity. Avoid administering tramadol to patients who are taking or have recently discontinued MAO inhibitors. Linezolid is an antibiotic with a weak and reversible MAO inhibitor activity, and concomitant use with tramadol can lead to serotonin syndrome.[27]

Mixed agonist or antagonist and partial agonists: The concomitant use of tramadol with mixed agonist or antagonist and partial agonists, such as butorphanol, nalbuphine, pentazocine, and buprenorphine, can reduce the analgesic effect of tramadol and precipitate withdrawal.

Muscle relaxants: Combining tramadol with skeletal muscle relaxants can potentiate neuromuscular blocking effects, increasing the risk of respiratory depression. Monitoring patients for respiratory depression to reduce the dosages of tramadol and muscle relaxants is important. The inclusion of naloxone should be considered for managing opioid overdose emergencies.

Diuretics: Opioids can decrease the efficacy of diuretics by increasing the release of antidiuretic hormone. Patients should be monitored for decreased diuresis and alterations in blood pressure, with adjustments made to the diuretic dose as needed.[28][29]

Anticholinergic drugs: The concomitant use of anticholinergics with opioids may increase the risk of urinary retention and paralytic ileus.[30]

Contraindications

Warnings and Precautions

Tramadol is contraindicated in patients who have had a hypersensitivity reaction to any opioid. Patients aged 12 or younger should not use the medication. Patients aged 18 or younger should not be given the drug if they have had a history of tonsillectomy or adenoidectomy. Because tramadol can cause respiratory depression, patients with a history of severe respiratory depression or bronchial asthma absent the necessary equipment should avoid taking tramadol. Patients currently on MAO inhibitors or those who have been on MAO inhibitors for 14 days should not receive tramadol.[5] People who have gastrointestinal obstruction should not use tramadol.

Box Warning

Respiratory depression: A risk of potentially life-threatening respiratory depression exists with opioids, including tramadol. The highest risk occurs during treatment initiation or after dosage increases, requiring careful observation within 24 to 72 hours. Close monitoring, supportive measures, and opioid antagonists may be necessary for managing the condition.

Educating patients and caregivers on identifying respiratory depression and the urgent need for medical assistance in case of overdose is essential. Discuss the availability of naloxone for emergency treatment of opioid overdose with patients and caregivers. Evaluate the necessity for naloxone access and provide information on obtaining naloxone as per state requirements and guidelines. Prescribe naloxone to patients at risk of overdose, considering factors like concomitant CNS depressant use, history of an opioid use disorder, or household members/close contacts at risk.[31]

Risk of medication errors: Ensure precision when prescribing, dispensing, and administering tramadol hydrochloride oral solution. Confirm that the tramadol dose is communicated and dispensed accurately. Dosing errors resulting from the confusion between milligrams (mg) and milliliters (mL) can result in unintentional overdose and fatalities. Strongly advise patients to calculate the tramadol hydrochloride oral solution dose using the calibrated dosing device and instruct patients against using household teaspoons or tablespoons.[32]

Addiction and misuse: Before prescribing tramadol, it is essential to evaluate each patient's risk of opioid addiction, abuse, and misuse, as these factors can contribute to overdose and fatalities. Clinicians must monitor patients for the emergence of opioid use disorder. Patients with a history of alcohol or substance use disorder are at higher risk for the potential hazards of opioid addiction.

However, these risks should not delay adequate pain management in any patient. In comparison, patients at increased risk may be prescribed opioids like tramadol, counseling about the risks, and appropriate use of tramadol when monitoring for signs of addiction and misuse. Opioids, including tramadol, may be subject to illicit diversion. Evaluate these risks when prescribing tramadol.

Strategies to mitigate these risks involve prescribing tramadol in low doses and advising patients on properly disposing of unused medication. Contact the state controlled substances authority or local state professional licensing board for guidance on preventing and detecting abuse or diversion of tramadol.[33][34]

Risk Evaluation and Mitigation Strategy (REMS) program: The FDA has instructed a REMS for opioids to ensure that the benefits of opioids outweigh the risks of misuse and addiction. Under the REMS prerequisites, pharmaceutical companies with approved opioid analgesic products must provide clinicians with education programs that comply with the REMS guidelines.[35]

Accidental ingestion: Ingestion of a single dose of tramadol tablet or solution by accident in children can lead to respiratory depression and potential fatality due to overdose.[36]

Opioids, including tramadol, can cause sleep-related breathing disorders such as central sleep apnea (CSA) and sleep-related hypoxemia. The risk of CSA is dose-dependent, warranting consideration of opioid dose reduction using evidence-based opioid tapering protocols in patients presenting with CSA.[37][38]

Neonatal opioid withdrawal syndrome: The prolonged use of tramadol during pregnancy can result in life-threatening neonatal opioid withdrawal syndrome. Immediate recognition, treatment, and management are necessary. If tramadol use is essential during pregnancy, inform the patient about the risk of neonatal opioid withdrawal syndrome and ensure the availability of appropriate treatment.[39]

Risks from the concomitant use of CNS depressants or benzodiazepines: Similar to anxiolytics, muscle relaxants, general anesthetics, antipsychotics, other opioids, and alcohol can cause profound sedation, respiratory depression, and potentially fatal outcomes.[40]

This combination should be limited to patients with no alternative treatment options. Close monitoring for signs of respiratory depression and sedation is crucial. Consider prescribing naloxone for opioid overdose. Educate patients on the risks and discourage activities such as driving or operating machinery. Assess for substance use disorders and caution patients about the heightened risk of overdose and mortality when combining tramadol with other CNS depressants, including alcohol and illicit drugs.[12]

Ultra-rapid metabolism of tramadol: Severe respiratory depression and mortalities have been documented in pediatric patients administered tramadol. Tonsillectomy and adenoidectomy procedures were associated with some of the reported incidents. In a case report, a child had evidence of an ultra-rapid metabolism of tramadol due to a CYP2D6 polymorphism. This is due to the increased concentration of active metabolite leading to toxicity. Avoid tramadol due to the potential for respiratory depression.[41][8]

Monitoring

Before administering tramadol, it is essential to get the patient's baseline liver function tests (aspartate aminotransferase, AST, and alanine transaminase, ALT) because the hepatic metabolism of the drug can lead to hepatotoxicity.[42] Recommendations include psychiatric evaluation for suicidal ideations or misuse of tramadol before prescribing the medication. Suicidal ideations are monitored, particularly during dose escalation or discontinuation.[43]

After administration, the clinician should continue to monitor the patient's liver function, blood pressure, respiratory system, and mental status. Due to the addictive potential of the drug, continued monitoring of the risks and benefits of tramadol use should occur every 3 months. Therapeutic drug monitoring is required for digoxin and warfarin. Cases of digoxin toxicity have been reported with simultaneous use of tramadol. Consider therapeutic drug monitoring of digoxin and adjust the digoxin dose as required. Occasional reports of elevation of prothrombin time have been reported with simultaneous use of tramadol. Monitor the prothrombin time/international normalized ratio (PT/INR) and adjust the warfarin dosage as needed.[44]

Toxicity

Signs and Symptoms of Overdose

Symptoms of opioid overdose, such as miosis, respiratory depression, and altered mental status, can be observed in cases of tramadol intoxication. In contrast to traditional opioids, tramadol can induce hypertension, tachycardia, and seizures. Severe poisoning can lead to multiorgan dysfunction, coma, and cardiopulmonary arrest.[45][46] In a retrospective cohort study of 6365 patients, 30-day mortality risk was lower in tramadol poisoning cases than morphine, oxycodone, and mixed poisonings.[47]

Management of Overdose

The initial treatment primarily is maintaining a patent airway and adequate ventilation through assisted or controlled ventilation.[48] As is the case with other opioids, naloxone can partially reverse the adverse effects of tramadol. Naloxone is a competitive antagonist of the mu-, kappa-, and sigma-type receptors that tramadol and other opioids bind to, with the highest affinity for the mu receptor. Naloxone is available in oral or IV formulations. The oral form has low bioavailability compared to the other formulations. The half-life of naloxone is shorter than tramadol, so repeat doses may be necessary. Although this drug may be used to decrease respiratory and CNS depression, it may increase the risk of seizures.[49][50]

Enhancing Healthcare Team Outcomes

Managing opioid overdose such as tramadol requires an interprofessional team effort involving numerous specialties, including medical toxicologists. Without proper management, an overdose of tramadol or other opioids can lead to death.

The process of treating tramadol overdose or misuse starts before initial administration. The incorrect use of prescriptions is a significant contributor to opioid use disorder, so the proper administration of the drug can help prevent drug use disorder. Pain management is vital in treating patients, and tramadol can provide valuable relief for this population.

Although tramadol has a comparatively low risk of misuse, cases of patients with no history of opioid use disorder develop the condition when taking the medication.[51] Therefore, reliance upon the interprofessional healthcare team, instead of just the prescribing clinician, is to prevent the misuse or toxicity of tramadol. The use of government policy changes that initiated prescription drug monitoring programs has resulted in decreased drug misuse as well as fewer drug fatalities.[52] 

Healthcare team members are essential in preventing the abuse of prescriptions. Case managers and nurses are vital in helping prevent prescribers from over-prescribing tramadol and other opioids. These functions are crucial in seeing the potential for use disorder in patients. They can help prevent opioid misuse by doing the following:

• Assessing the clinical need for medication

• Identifying treatment and other available resources.

• Providing education and support to the patient and their family.

• Identifying drug-seeking habits.[53]

Pharmacists are also critical in the management of tramadol abuse. They can help prevent the misuse of prescriptions by:

• Providing education on how to take their medication.

• Preventing prescription falsifications.

• Recognizing problematic signs of drug use and prescription filling, such as "doc shopping."

The nursing staff is also integral in managing tramadol therapy, serving as initial contact points for the prescribing clinician and answering questions regarding dosing, administration, and adverse events. They provide patient counseling on medication administration, closely monitor for adverse events, and evaluate treatment effectiveness. Effective communication and collaboration among healthcare team members ensure timely addressing and reporting any issues or concerns to prescribing clinicians. An interprofessional team approach involving prescribing clinicians, specialists, nurses, pharmacists, toxicologists, and case managers is essential for optimizing pain management outcomes with tramadol while minimizing the risk of adverse drug reactions.