Tramadol

Tramadol is an opioid painkiller (narcotic analgesic) used for the short-term relief of moderate to severe pain, including pain after surgery ¹, ², ³, ⁴. Tramadol is also used to treat pain severe enough to require opioid treatment and when other pain medicines did not work well enough or cannot be tolerated. Tramadol immediate-release tablets and oral solution are used as a short-term treatment to relieve severe pain (pain that begins suddenly, has a specific cause, and is expected to go away when the cause of the pain is healed) in people who are expected to need an opioid pain medication and who cannot be controlled by the use of alternative pain medications. The tramadol extended-release capsules and tablets are used for severe and persistent pain in people who are expected to need an opioid pain medication to relieve pain around-the-clock for a long time and who cannot be treated with other pain medications. Tramadol extended-release tablets and capsules should not be used to treat mild or moderate pain, short-term pain, or pain that can be controlled by medication that is taken as needed. Tramadol may be habit forming, especially with prolonged use. If you stop taking tramadol suddenly, you may experience withdrawal symptoms, so ask your doctor how to reduce your dose safely.

Tramadol was approved for use in the United States in 1995 and is currently widely used, with more than 18 million prescriptions written yearly. Tramadol is only available with a prescription from your doctor and tramadol is classified as a Schedule IV controlled substance and is provided under a risk evaluation and mitigation strategy (REMS) ⁵. Tramadol contraindicated in children below the age of 12 because of risk of respiratory depression, and prolonged use should be avoided in pregnancy because of the risk of infant withdrawal syndrome.

Tramadol is in a class of medications called opiate (narcotic) analgesics. Tramadol is a synthetic codeine analog that acts as a weak opioid agonist in addition to mildly inhibiting serotonin and norepinephrine reuptake in your brain and spinal cord (central nervous system). Tramadol is a mu (μ) opioid receptor agonist and norepinephrine and serotonin reuptake inhibitor. Similar to other opioids, tramadol selectively binds to various opiate receptors in the central nervous system (brain and spinal cord) due to its opioid nature. The liver enzyme CYP2D6 converts tramadol to its active metabolite M1 (O-desmethyl-tramadol), which has a stronger affinity for the mu (μ) opioid receptor than the inactive form (tramadol) ⁴. The mu (μ) opioid receptor also called mu-opioid receptor (MOR) is a type of G protein-coupled receptor that binds opioids and plays a key role in pain relief (analgesia) and the rewarding effects of drugs like morphine and heroin, which can lead to addiction ⁶. The mu receptor (MOR) also mediates side effects such as sedation and respiratory depression and influences mood, stress, and gastrointestinal function. Activation of the mu receptor (MOR) by its endogenous ligands, such as endorphins, or by opioid drugs, triggers signaling pathways that modulate physiological responses. The M1 metabolite (O-desmethyl-tramadol) is up to 6 times more potent than tramadol in producing analgesia. Tramadol does not bind to the mu receptor (MOR) as much as morphine. Unlike other opioids, tramadol does not reverse its course completely following naloxone administration ⁷. The analgesic effect of tramadol is also attributed to the antinociceptive effect in the descending pathway, secondary to the inhibition of serotonin and norepinephrine reuptake ⁸.

Tramadol comes as an immediate-release tablet, a solution (liquid), an extended-release (long-acting) tablet, and an extended-release (long-acting) capsule to take by mouth. Tramadol is also available as tablets of 37.5 mg in combination with acetaminophen (325 mg) both generically and under the brand name Ultracet. The immediate-release tramadol tablet and solution are taken usually with or without food every 4 to 6 hours as needed (usually for no more than a few days). The usual tramadol dose in adults is initially 25 mg daily, with titration based on effect and tolerance to 50 to 100 mg every 4 to 6 hours as needed for pain, but not to exceed 400 mg daily. The extended-release tramadol tablet and extended-release tramadol capsule of 100, 200 and 300 mg are also available (ConZip and generics) and are given once daily. Take the extended-release tablet and the extended-release capsule at about the same time of day every day. If you are taking the extended-release tablet or extended-release capsule, you should take it consistently, either always with or always without food. Take tramadol exactly as directed. Do not take more medication as a single dose or take more doses per day than prescribed by your doctor. Taking more tramadol than prescribed by your doctor or in a way that is not recommended may cause serious side effects or death.

Your doctor may start you on a low dose of tramadol and gradually increase the amount of medication you take, not more often than every 3 days if you are taking the solution or regular tablets or every 5 days if you are taking the extended-release tablets or extended-release capsules.

If you are taking the solution, use an oral syringe or measuring spoon or cup to measure the correct amount of liquid needed for each dose. Do not use a regular household spoon to measure your dose. Ask your doctor or pharmacist if you need help getting or using a measuring device,

Do not stop taking tramadol without talking to your doctor. Your doctor will probably decrease your dose gradually. If you suddenly stop taking tramadol, you may experience withdrawal symptoms such as nervousness; panic; sweating; difficulty falling asleep or staying asleep; runny nose, sneezing, or cough; pain; hair standing on end; chills; nausea; uncontrollable shaking of a part of your body; diarrhea; or rarely, hallucinations (seeing things or hearing voices that do not exist).

Tell your doctor if your pain increases, gets worse, or if you have new pain or an increased sensitivity to pain, especially after taking tramadol. Do not take more of it or take it more often than prescribed by your doctor.

The most common side effects of tramadol are nausea, vomiting, dizziness, itch, anorexia, constipation, sleepiness, dry mouth, sedation, seizures, low blood pressure (hypotension) and headache which may occur in therapeutic or toxic doses ⁹. These tramadol side effects tend to occur during the initial treatment rather than the maintenance phase ¹⁰. Tramadol-induced mania has been reported in a patient with no history of bipolar disorder ¹¹. Other rare but potentially severe adverse events include seizures, severe respiratory depression, serotonin syndrome, addiction, abuse and withdrawal syndrome.

Serious adverse effects of tramadol include profound sedation and respiratory depression, the latter of which, if severe, may result in death. The most common mechanisms of death after tramadol overdose are cardiorespiratory depression, resistant shock, asystole, and liver failure. Fatal toxicity of tramadol has been reported after coadministration of other medications including propranolol, ethanol, barbiturates, and benzodiazepines.

Tramadol may also cause Tramadol Induced Adrenal Insufficiency, a condition where the adrenal glands produce insufficient amounts of steroid hormones, including cortisol and aldosterone ¹². Adrenal insufficiency requires prompt diagnosis, discontinuation of tramadol, and treatment with steroids ¹². Severe low blood pressure (hypotension), fainting, and postural hypotension (a form of low blood pressure that occurs when a person’s blood pressure drops suddenly after sitting up or standing from a lying-down position) have also been reported. Tramadol can reduce respiratory drive, leading to CO2 retention and exacerbating pressure inside your skull (intracranial pressure). Use tramadol cautiously in patients with brain tumors,  traumatic brain injury (TBI) or with raised intracranial pressure ¹³.

How long to take tramadol for?

How long to take tramadol for depends on why you’re taking tramadol or your medical condition. You may only need to take tramadol for a short time. For example, if you’re in pain after an injury or surgery, you may only need to take tramadol for a few days or weeks at most.

You may need to take tramadol for longer if you have a long-term condition.

Talk to your doctor if you’re unsure how long you need to take tramadol for.

If you need to take tramadol for a long time your body can become used to it. This is not usually a problem but you could get unpleasant withdrawal symptoms if you stop taking it suddenly.

If you want to stop taking tramadol, talk to your doctor first. Your dose will usually be reduced gradually so you do not get withdrawal effects.

Tramadol can cause unpleasant withdrawal symptoms if you come off it suddenly, such as:

• feeling agitated
• feeling anxious
• shaking
• sweating

How does tramadol work?

Tramadol is in a class of medications called opiate (narcotic) analgesics. Tramadol is a synthetic codeine analog that acts as a weak opioid agonist in addition to mildly inhibiting serotonin and norepinephrine reuptake in your brain and spinal cord (central nervous system). Similar to other opioids, tramadol selectively binds to various opiate receptors in the central nervous system (brain and spinal cord) due to its opioid nature. The liver enzyme CYP2D6 converts tramadol to its active metabolite M1 (O-desmethyl-tramadol), which has a stronger affinity for the mu (μ) opioid receptor than the inactive form (tramadol) ⁴. The mu (μ) opioid receptor also called mu-opioid receptor (MOR) is a type of G protein-coupled receptor that binds opioids and plays a key role in pain relief (analgesia) and the rewarding effects of drugs like morphine and heroin, which can lead to addiction ⁶. The mu receptor (MOR) also mediates side effects such as sedation and respiratory depression and influences mood, stress, and gastrointestinal function. Activation of the mu receptor (MOR) by its endogenous ligands, such as endorphins, or by opioid drugs, triggers signaling pathways that modulate physiological responses. The M1 metabolite (O-desmethyl-tramadol) is up to 6 times more potent than tramadol in producing analgesia. Tramadol does not bind to the mu receptor (MOR) as much as morphine. Unlike other opioids, tramadol does not reverse its course completely following naloxone administration ⁷.

The analgesic effect of tramadol is also attributed to the antinociceptive effect in the descending pathway, secondary to the inhibition of serotonin and norepinephrine reuptake ⁸.

Pharmacokinetics

Absorption: The average absolute bioavailability of tramadol 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. Individuals who have reduced CYP2D6 activity are known as “intermediate metabolizers” and those with absent CYP2D6 activity are known as “poor metabolizers” ⁴. The standard recommended doses of tramadol may not provide adequate pain relief in these individuals (“poor metabolizers”) because of reduced levels of M1 metabolite formation compared to individuals with normal CYP2D6 activity ¹⁴, ⁴. Whereas in individuals who have increased CYP2D6 activity (“ultrarapid metabolizers”), standard doses of tramadol may result in a higher risk of adverse events because of increased exposure to M1 metabolite formation compared to individuals with normal CYP2D6 activity ⁴. The 2021 FDA-approved drug label warns that individuals who are ultrarapid metabolizers of tramadol should not use tramadol because of the risk of life-threatening respiratory depression and signs of opiate overdose (for example, extreme sleepiness, confusion, or shallow breathing) ¹⁵.

The prevalence of CYP2D6 Ultrarapid Metabolizer (a genetic trait where an individual has an enhanced ability to break down tramadol to active M1 metabolite) varies but is thought to be present in approximately 1–10% of Caucasians (European, North American), 3–4% of Blacks (African Americans), and 1–2% of East Asians (Chinese, Japanese, Korean) ⁴. The frequency of CYP2D6 Ultrarapid Metabolizer phenotype has been reported to be even higher in some groups, including Ashkenazi Jews and regional populations in the Middle East.

Furthermore, tramadol is not recommended in nursing mothers due to the potential exposure to high levels of M1 metabolite (O-desmethyl-tramadol) causing life-threatening respiratory depression, if the mother is a CYP2D6 Ultrarapid Metabolizer. At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an CYP2D6 Ultrarapid Metabolizer of codeine, which—similar to tramadol—is activated by CYP2D6 metabolism.

Tramadol is contraindicated for all children younger than age 12 and for all individuals under the age of 18 when being used for post-operative analgesia following tonsillectomy or adenoidectomy, or both. The label warns that life-threatening respiratory depression and death have occurred in children who received tramadol, and in at least one case, the child was an CYP2D6 Ultrarapid Metabolizer of tramadol.

The Clinical Pharmacogenetics Implementation Consortium recommends that for an individual identified as a CYP2D6 Ultrarapid Metabolizer, a different non-CYP2D6 dependent analgesic should be used to avoid the risk of severe toxicity with standard dosing of tramadol ¹⁶. The Clinical Pharmacogenetics Implementation Consortium also recommends avoiding tramadol in individuals identified as CYP2D6 poor metabolizers (PMs) due to the possibility of lack of effect ¹⁶.

The Dutch Pharmacogenetics Working Group of the Royal Dutch Association for the Advancement of Pharmacy provides dosing recommendations for tramadol based on CYP2D6 genotype ¹⁷. The Dutch Pharmacogenetics Working Group states it is not possible to calculate a dose adjustment for tramadol, because when the ratio of tramadol and M1 metabolite (O-desmethyl-tramadol) is altered, the nature and total analgesic effect of tramadol also changes. For CYP2D6 Ultrarapid Metabolizer, the Dutch Pharmacogenetics Working Group recommends selecting an alternative drug to tramadol – but not codeine, which is also metabolized by CYP2D6. Alternative drugs include morphine (not metabolized by CYP2D6) and oxycodone (which is metabolized by CYP2D6 to a limited extent, but this does not result in differences in side effects in clinical practice). For CYP2D6 poor (“poor metabolizers”) and intermediate metabolizers (“intermediate metabolizers”), the Dutch Pharmacogenetics Working Group recommends increasing the dose of tramadol, and if this does not have the desired effect, selecting an alternative drug (not codeine) ¹⁷.

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 ¹⁸.

Tramadol special precautions

Before taking tramadol:

• tell your doctor and pharmacist if you are allergic to tramadol, other opiate pain medications, any other medications, or any of the ingredients in tramadol tablets, capsules, and oral solution. Ask your pharmacist for a list of the ingredients.
• tell your doctor or pharmacist if you are taking or receiving the following medications or if you have stopped taking them within the past 2 weeks: isocarboxazid (Marplan), linezolid (Zyvox), methylene blue, phenelzine (Nardil), selegiline (Emsam, Zelapar), or tranylcypromine (Parnate).
• The following nonprescription or herbal products may interact with tramadol: St. John’s wort and tryptophan. Be sure to let your doctor and pharmacist know that you are taking these medications before you start taking tramadol. Do not start these medications while taking tramadol without discussing it with your healthcare provider.
• tell your doctor if you have any of the conditions mentioned in the IMPORTANT WARNING section, a blockage or narrowing of your stomach or intestines, or paralytic ileus (condition in which digested food does not move through the intestines). Your doctor may tell you not to take tramadol if you have any of these conditions.
• tell your doctor if you have or have ever had seizures; an infection in your brain or spine; difficulty urinating; low blood levels of sodium; thoughts about harming or killing yourself or planning or trying to do so; diabetes; pancreas, gall bladder, or thyroid problems; or kidney or liver disease.
• tell your doctor if you are breastfeeding. You should not breastfeed while taking tramadol. Tramadol can cause shallow breathing, difficulty or noisy breathing, confusion, more than usual sleepiness, trouble breastfeeding, or limpness in breastfed infants.
• you should know that this medication may decrease fertility in men and women. Talk to your doctor about the risks of taking tramadol.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking tramadol.
• you should know that this medication may make you drowsy and may affect your coordination. Do not drive a car or operate machinery until you know how this medication affects you.
• you should know that tramadol may cause dizziness, lightheadedness, and fainting when you get up from a lying position. To avoid this, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.
• you should know that tramadol may cause constipation. Talk to your doctor about changing your diet and using other medications to treat or prevent constipation.

Before administering tramadol, it is essential to get the patient’s baseline liver function tests (aspartate aminotransferase [AST], and alanine transaminase [ALT]) because the liver metabolism of tramadol can lead to liver toxicity ². 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 ¹⁹.

After administering tramadol, the clinician should continue to monitor the patient’s liver function, blood pressure, respiratory system, and mental status. Due to the addictive potential of tramadol, 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 (PT) have been reported with simultaneous use of tramadol. Monitor the prothrombin time/international normalized ratio (PT/INR) and adjust the warfarin dosage as needed ²⁰.

Elderly

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of tramadol in the elderly. However, elderly patients are more likely to have unwanted side effects (eg, constipation, lightheadedness, dizziness, or fainting, stomach upset, weakness) and age-related liver, kidney, heart, or lung problems, which may require caution and an adjustment in the dose for patients receiving tramadol. The maximum recommended daily dosage for immediate-release formulation is 300 mg. Tramadol extended-release formulation should be used cautiously.

Pregnant mothers

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 ²¹. According to American College of Obstetricians and Gynecologists (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 ²².

Breastfeeding mothers

Studies in women breastfeeding have demonstrated harmful infant effects. An alternative to this medication should be prescribed or you should stop breastfeeding while using tramadol. 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 ²³.

Drug-Drug Interactions

Using tramadol with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Isocarboxazid
• Linezolid
• Mavorixafor
• Methylene Blue
• Moclobemide
• Naltrexone
• Ozanimod
• Phenelzine
• Procarbazine
• Rasagiline
• Safinamide
• Samidorphan
• Selegiline
• Tranylcypromine

Using tramadol with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

Using tramadol with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Desflurane

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 ²⁴.

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 ²⁵.

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 ²⁶.

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 ²⁷.

Monoamine oxidase inhibitors (MAOIs)

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 ²⁸.

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 (water pills)

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 ²⁹, ³⁰.

Anticholinergic drugs

The concomitant use of anticholinergics with opioids may increase the risk of urinary retention and paralytic ileus (a temporary, non-mechanical blockage of the intestines where the normal muscle contractions that move food and fluid stop or significantly slow, leading to symptoms like bloating, nausea, vomiting, and constipation) ³¹.

Other Medical Problems

The presence of other medical problems may affect the use of tramadol. Make sure you tell your doctor if you have any other medical problems, especially:

• Adrenal problems
• Alcohol abuse or history of alcohol abuse
• Brain tumor
• Depression or history of depression
• Diabetes
• Drug abuse or dependence or history of drug abuse or dependence
• Gallstones
• Head injury
• Hormonal problems
• Increased pressure in the head
• Infections of the central nervous system (brain and spinal cord)
• Lung or breathing problems (eg, COPD, cor pulmonale, hypercapnia, hypoxia, sleep apnea)
• Mental illness (eg, suicidal ideation) or history of mental illness
• Phenylketone allergy or history of phenylketone allergy
• Seizures or epilepsy or history of seizures or epilepsy
• Stomach problems, severe. Use with caution. May increase risk for more serious side effects.
• Asthma
• Lung or breathing problems
• Stomach or bowel blockage (eg, paralytic ileus)
• Surgery (eg, nasopharyngeal tonsils, tonsils). Should not be used in patients with these conditions.
• Kidney disease
• Liver disease (including cirrhosis). Use with caution. The effects may be increased because of slower removal of tramadol from the body.

Tramadol Contraindications

Tramadol is contraindicated in patients who have had a hypersensitivity reaction to any opioid. Patients aged 12 or younger should not use tramadol. Patients aged 18 or younger should not be given tramadol 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 (antidepressant medications that block the monoamine oxidase [MAO] enzyme, which breaks down neurotransmitters like dopamine, serotonin, and norepinephrine) or those who have been on MAO inhibitors for 14 days should not receive tramadol ⁷. 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 ³².

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 ³³.

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 ³⁴, ³⁵.

Risk Evaluation and Mitigation Strategy (REMS) program: The FDA has instructed a Risk Evaluation and Mitigation Strategy (REMS) for opioids to ensure that the benefits of opioids outweigh the risks of misuse and addiction. Under the Risk Evaluation and Mitigation Strategy (REMS) prerequisites, pharmaceutical companies with approved opioid analgesic products must provide clinicians with education programs that comply with the Risk Evaluation and Mitigation Strategy (REMS) guidelines ³⁶.

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 ³⁷.

Tramadol-induced apnea and central sleep apnea. Opioids, including tramadol, can cause sleep-related breathing disorders such as central sleep apnea (a sleeping and breathing disorder where the brain fails to send proper signals to the breathing muscles, causing breathing to repeatedly stop and restart during sleep) and sleep-related hypoxemia (a condition where blood oxygen levels drop to abnormally low levels during sleep, often due to underlying medical problems like sleep apnea or lung disease). The risk of central sleep apnea is dose-dependent, warranting consideration of opioid dose reduction using evidence-based opioid tapering protocols in patients presenting with central sleep apnea ³⁸, ³⁹.

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 ⁴⁰.

Risks from the concomitant use of central nervous system (CNS) depressants or benzodiazepines with tramadol: Similar to anxiolytics, muscle relaxants, general anesthetics, antipsychotics, other opioids, and alcohol can cause profound sedation, respiratory depression, and potentially fatal outcomes ⁴¹. 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 ⁴².

Ultra-rapid metabolism of tramadol: Severe respiratory depression and mortalities have been documented in children 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 genetic mutation (CYP2D6 Ultrarapid Metabolizer). This is due to the increased concentration of active M1 metabolite (O-desmethyl-tramadol) leading to toxicity. Avoid tramadol due to the potential for respiratory depression ⁴, ¹⁶.

Tramadol uses

Tramadol is used in adults to relieve moderate to moderately severe pain, including pain after surgery for which alternative treatments are inadequate. Tramadol is also used to treat pain severe enough to require opioid treatment and when other pain medicines did not work well enough or cannot be tolerated. The extended-release capsules or tablets are used for chronic ongoing pain.

However, because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration, reserve tramadol for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products):

• Have not been tolerated or are not expected to be tolerated.
• Have not provided adequate analgesia or are not expected to provide adequate analgesia.

Tramadol should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

When tramadol is used for a long time, it may become habit-forming, causing mental or physical dependence. However, people who have continuing pain should not let the fear of dependence keep them from using narcotics to relieve their pain. Mental dependence (addiction) is not likely to occur when narcotics are used for this purpose. Physical dependence may lead to withdrawal side effects if treatment is stopped suddenly. However, severe withdrawal side effects can usually be prevented by gradually reducing the dose over a period of time before treatment is stopped completely.

Tramadol is available only under a restricted distribution program called the Opioid Analgesic REMS (Risk Evaluation and Mitigation Strategy) program.

FDA-Approved Indications

Tramadol is approved by the US Food and Drug Administration (FDA) as a pain relief medication, specifically indicated for moderate-to-severe pain. Since July 2014, the FDA has classified tramadol as a class IV controlled substance due to its potential for misuse and addiction. Therefore, its use is restricted to cases of pain refractory to other medications, such as nonopioid pain medication.

Immediate-release tramadol is not intended for use as an “as needed” medication but rather for pain episodes lasting less than a week. In contrast, extended-release tramadol is the preferred choice for pain persisting beyond a week, and its indication lies in providing 24-hour pain management or prolonged relief.

Off-Label Uses

Tramadol has off-label uses for premature ejaculation and restless leg syndrome that are refractory to other medications ⁴³, ⁴⁴. According to American Urological Association, tramadol is not a first-line therapy, but clinicians may consider low-dose tramadol to treat premature ejaculation unresponsive to first-line drug therapies ⁴⁵. A recent meta-analysis revealed that 25 to 50 mg tramadol “on-demand” taken before intercourse is effective for premature ejaculation ⁴⁵, ⁴⁶, ⁴⁷.

For the off-label use of tramadol for premature ejaculation, both sporadic and daily administration have been found effective in treating the condition. Patients often prefer “as needed” therapy for premature ejaculation due to the reduced risk of adverse effects compared to daily tramadol use ⁴⁸. However, considering the opioid epidemic and concerns regarding misuse potential, off-label use is not recommended.

Tramadol dosage

Tramadol is available and used in 2 solid formulations—extended release and immediate release. Both the extended-release and immediate-release tramadol 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 ⁴⁹. 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.

Tramadol is available in various dosages:

• Standard tablets – these contain 50mg of tramadol
• Slow-release (extended release) tablets – these contain 50mg, 75mg, 100mg, 150mg, 200mg, 300mg or 400mg of tramadol
• Standard capsules – these contain 50mg of tramadol
• Slow-release (extended release) capsules – these contain 50mg, 100mg, 150mg or 200mg of tramadol
• Drops that you swallow – this contains 100mg of tramadol in 1ml of liquid
• Tramadol solution – this contains 5 mg tramadol/mL
• Soluble (immediate release) tablets – these contain 50mg of tramadol
• Tablets that dissolve in your mouth (orodispersible) – these contain 50mg of tramadol
• An injection (usually given in hospital)

Tramadol dosages vary from person to person. Your doctor will decide the right tramadol dose for you, depending on how sensitive you are to pain, how bad your pain is, how you responded to previous painkillers (analgesics) and if you get any side effects.

Your dose may need to be changed several times to find what works best for you. In general, you will be prescribed the lowest tramadol dose that relieves your pain.

Take tramadol only as directed by your doctor. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. This is especially important for elderly patients, who may be more sensitive to the effects of pain medicines. If too much of tramadol is taken for a long time, it may become habit-forming (causing mental or physical dependence) or cause an overdose.

It is very important that you understand the rules of the Opioid Analgesic REMS program to prevent addiction, abuse, and misuse of tramadol. This medicine should come with a Medication Guide. Read and follow the instructions carefully. Read it again each time you refill your prescription in case there is new information. Ask your doctor if you have any questions.

If you think that tramadol is not working as well after you have been taking it for a few weeks, do not increase the dose. Instead, check with your doctor.

Swallow the extended-release capsule, extended-release tablet, and tablet whole with liquids. Do not break, crush, chew, snort, or inject it.

Measure the oral liquid with the marked dosing syringe that comes with the package. Your dose needs to be measured and given accurately to avoid an overdose.

Acute pain

The recommended daily dosage of immediate-release tramadol is 50 mg and 100 mg every 4 to 6 hours as needed for pain. The maximum recommended dosage of tramadol is 400 mg/day ⁵⁰.

For moderate to severe pain:

• For oral dosage form (solution): For adults not requiring rapid onset of analgesic effect, at first, 25 milligrams (mg) once a day. Your doctor may increase your dose as needed. Titrate in 25 mg increments every 3 days to reach a dose of 25 mg four times a day; thereafter increase by 50 mg as tolerated every 3 days. However, the dose is usually not more than 400 mg per day.
• For oral dosage form (tablets): 
  • For adults not requiring rapid onset of analgesic effect, at first, 25 milligrams (mg) per day, taken every morning. Your doctor may increase your dose as needed and tolerated. However, the dose is usually not more than 400 mg per day.
  • Older adults over 75 years of age: At first, 25 mg per day, taken every morning. Your doctor may increase your dose as needed and tolerated. However, the dose is usually not more than 300 mg per day.

Chronic non-cancer pain

According to the U.S. Centers for Disease Control and Prevention (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 ⁴². 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 ⁵¹.

For chronic pain:

• For oral dosage form (extended-release capsules): Adults, at first, 100 milligrams (Extended-Release) once a day. Your doctor may increase your dose as needed. Individually titrate in 100 mg increments every 5 days to an effective dose that minimizes adverse reactions. However, the dose is usually not more than 300 mg per day.
• For oral dosage form (extended-release tablets): Adults, at first, 100 milligrams (Extended-Release) once a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 300 mg per day.

Premature ejaculation (off-label)

According to American Urological Association, tramadol is not a first-line therapy, but clinicians may consider low-dose tramadol to treat premature ejaculation unresponsive to first-line drug therapies ⁴⁵. A recent meta-analysis revealed that 25 to 50 mg tramadol “on-demand” taken before intercourse is effective for premature ejaculation ⁴⁵, ⁴⁶, ⁴⁷.

Specific Patient Populations

Liver 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).

Kidney 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 ²¹. According to American College of Obstetricians and Gynecologists (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 ²².

Breastfeeding considerations: Studies in women breastfeeding have demonstrated harmful infant effects. An alternative to this medication should be prescribed or you should stop breastfeeding while using tramadol. 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 ²³.

Children: 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: Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of tramadol in the elderly. However, elderly patients are more likely to have unwanted side effects (eg, constipation, lightheadedness, dizziness, or fainting, stomach upset, weakness) and age-related liver, kidney, heart, or lung problems, which may require caution and an adjustment in the dose for patients receiving tramadol. The maximum recommended daily dosage for immediate-release formulation is 300 mg. Tramadol extended-release formulation should be used cautiously.

What happens if I miss a dose?

If your doctor has told you to take tramadol regularly, take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

How and when to take tramadol

Follow your doctor’s instructions about how to use tramadol. This is particularly important because tramadol can be addictive.

Tramadol drops, injections and some tablets and capsules will start to work within 30 to 60 minutes. They’re used for pain that is expected to last for only a short time. You may be told to take this type of tramadol only if you need it for pain that can come and go.

How to take standard tablets and capsules

Swallow each tablet or capsule whole with a glass of water.

How to take drops

Mix the drops into a glass of water then drink the whole contents of the glass.

How to take soluble tablets

Dissolve each tablet in a drink of water (more than a mouthful or a sip) and drink

How to take tablets that dissolve in the mouth

Make sure your hands are dry before handling the tablet. Pop the tablet out of its pack and put it on your tongue. Suck the tablet, do not chew it. After it has melted, swallow or have a drink of water. You can also dissolve the tablet in a glass of water if you prefer.

How to take slow-release tablets and capsules

It’s important to swallow slow-release tramadol tablets and capsules whole with a drink of water.

Slow-release tablets and capsules release the medicine into your body over either 12 or 24 hours. This type of tramadol takes longer to start working but lasts longer. It’s used for long-term pain.

When to take tramadol

When to take it depends on the type of tramadol that you have been prescribed:

• Standard tramadol tablets and capsules – usually 3 to 4 times a day
• Tramadol Drops – usually 3 to 4 times a day
• Tramadol slow-release tablets and capsules – usually once or twice a day

If you’re 65 or over, or you have liver or kidney problems, your doctor may ask you to take tramadol less often.

You can take your tramadol at any time of day but try to take it at the same time every day, and space your doses evenly. For example, if you take tramadol twice a day and have your first dose at 8am, take your second dose at 8pm.

Tramadol side effects

Tramadol may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• sleepiness
• headache
• nervousness
• uncontrollable shaking of a part of the body
• changes in mood
• heartburn or indigestion
• dry mouth

Some side effects can be serious. If you experience any of these symptoms or those mentioned in the IMPORTANT WARNING section, call your doctor immediately or get emergency medical treatment:

• hives
• rash
• blisters
• hoarseness
• difficulty swallowing or breathing
• chest pain
• swelling of the eyes, face, throat, tongue, lips, hands, feet, ankles, or lower legs
• agitation, hallucinations (seeing things or hearing voices that do not exist), fever, sweating, confusion, fast heartbeat, shivering, severe muscle stiffness or twitching, loss of coordination, or diarrhea
• nausea, vomiting, loss of appetite, fatigue, weakness, or dizziness
• changes in heartbeat
• headache, confusion, loss of energy, drowsiness, restlessness, muscle weakness, spasms or cramps
• hunger, shaking of a part of your body that you cannot control, irritability, or difficulty concentrating
• loss of consciousness
• seizures.

Tramadol may also cause Tramadol Induced Adrenal Insufficiency, a condition where the adrenal glands produce insufficient amounts of steroid hormones, including cortisol and aldosterone ¹². Adrenal insufficiency requires prompt diagnosis, discontinuation of tramadol, and treatment with steroids ¹². Severe low blood pressure (hypotension), fainting, and postural hypotension (a form of low blood pressure that occurs when a person’s blood pressure drops suddenly after sitting up or standing from a lying-down position) have also been reported. Tramadol can reduce respiratory drive, leading to CO2 retention and exacerbating pressure inside your skull (intracranial pressure). Use tramadol cautiously in patients with brain tumors,  traumatic brain injury (TBI) or with raised intracranial pressure ¹³.

Tramadol may cause other side effects. Tell your doctor if you have any unusual problems while you are taking tramadol.

Tramadol overdose

Symptoms of opioid overdose, such as miosis, respiratory depression, and altered mental status, can be observed in cases of tramadol overdose.

Symptoms of tramadol overdose may include the following:

• decreased size of the pupil (the black circle in the center of the eye)
• difficulty breathing
• slow or shallowing breathing
• extreme drowsiness or sleepiness
• unable to respond or wake up
• slowed heartbeat
• muscle weakness
• cold, clammy skin.

In contrast to traditional opioids, tramadol can also induce high blood pressure (hypertension), fast heart rate (tachycardia), and seizures. Severe tramadol overdose can lead to multiorgan dysfunction, coma, and cardiopulmonary arrest ⁵², ⁵³.

In case of tramadol overdose, call the poison control helpline at 1-800-222-1222. If the victim has collapsed, had a seizure, has trouble breathing, or can’t be awakened, immediately call your local emergency services number.

In a retrospective cohort study of 6365 patients, 30-day mortality risk was lower in tramadol overdose cases than morphine, oxycodone, and mixed poisonings ⁵⁴.

Tramadol Overdose Management

The initial treatment primarily is maintaining a patent airway and adequate ventilation through assisted or controlled ventilation ⁵⁵. 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 opiod 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 Naloxone has low bioavailability compared to the other formulations. The half-life of naloxone is shorter than tramadol, so repeat doses may be necessary. Although Naloxone may be used to decrease respiratory and central nervous system depression, it may increase the risk of seizures ⁵⁶, ⁵⁷.

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