Tramadol, sold under the brand name Tramal among others, is an

opioid Opioids are a class of Drug, drugs that derive from, or mimic, natural substances found in the Papaver somniferum, opium poppy plant. Opioids work on opioid receptors in the brain and other organs to produce a variety of morphine-like effects, ...

pain medication An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in so ...

and a

serotonin–norepinephrine reuptake inhibitor Serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications used to treat major depressive disorder (MDD), anxiety disorders, social phobia, chronic neuropathic pain, fibromyalgia syndrome (FMS), and menopaus ...

(SNRI) used to treat moderately severe

pain Pain is a distressing feeling often caused by intense or damaging Stimulus (physiology), stimuli. The International Association for the Study of Pain defines pain as "an unpleasant sense, sensory and emotional experience associated with, or res ...

. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour. It is also available by injection. It is available in combination with

paracetamol Paracetamol, or acetaminophen, is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. It is a widely available over-the-counter drug sold under various brand names, including Tylenol and Panadol. Parac ...

(acetaminophen). As is typical of opioids, common side effects include

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The Human feces, stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the ...

itchiness An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...

, and

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

. Serious side effects may include

hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

s, increased risk of

serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain Serotonin, serotonergic medications or Recreational drug use, drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild c ...

, decreased alertness, and

drug addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...

. A change in dosage may be recommended in those with

kidney In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...

or liver problems. It is not recommended in those who are at risk of

suicide Suicide is the act of intentionally causing one's own death. Risk factors for suicide include mental disorders, physical disorders, and substance abuse. Some suicides are impulsive acts driven by stress (such as from financial or ac ...

or in those who are

pregnant Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

. While not recommended in women who are

breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...

, those who take a single dose should not generally have to stop breastfeeding. Tramadol is converted in the liver to ''O''-desmethyltramadol (desmetramadol), an opioid with a stronger affinity for the

μ-opioid receptor The μ-opioid receptors (MOR) are a class of opioid receptors with a high affinity for enkephalins and beta-endorphin, but a low affinity for dynorphins. They are also referred to as μ(''mu'')-opioid peptide (MOP) receptors. The prototypical ...

. Tramadol was patented in 1972 and launched under the brand name Tramal in 1977 by the West German

pharmaceutical company The pharmaceutical industry is a Medicine, medical industry that discovers, develops, produces, and markets pharmaceutical goods such as medications and medical devices. Medications are then administered to (or Self-medicate, self-administered b ...

Grünenthal GmbH Grünenthal GmbH is a pharmaceutical company headquartered in Aachen in Germany. It was founded in 1946 as Chemie Grünenthal and has been continuously family-owned. The company was the first to introduce penicillin into the German market in t ...

. In the mid-1990s, it was approved in the United Kingdom and the United States. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...

and marketed under many brand names worldwide. In 2022, it was the 55th most commonly prescribed medication in the United States, with more than 12million prescriptions.

Medical uses

Tramadol is used primarily to treat mild to severe pain, both acute and chronic. There is moderate evidence for use as a second-line treatment for

fibromyalgia Fibromyalgia (FM) is a functional somatic syndrome with symptoms of widespread chronic pain, accompanied by fatigue, sleep disturbance including awakening unrefreshed, and Cognitive deficit, cognitive symptoms. Other symptoms can include he ...

, but it is not

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

-approved for this use. Its use is approved for treatment of fibromyalgia as a secondary

painkiller An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

by the

NHS The National Health Service (NHS) is the term for the publicly funded health care, publicly funded healthcare systems of the United Kingdom: the National Health Service (England), NHS Scotland, NHS Wales, and Health and Social Care (Northern ...

. Its

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

effects take approximately an hour to be realized, and it takes from two to four hours to reach peak effect after oral administration with an immediate-release formulation. On a dose-by-dose basis, tramadol has about one-tenth the potency of

morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...

(thus 100 mg is commensurate with 10 mg morphine but may vary) and is practically equally potent when compared with

pethidine Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a fully synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemist Ot ...

and

codeine Codeine is an opiate and prodrug of morphine mainly used to treat pain, coughing, and diarrhea. It is also commonly used as a recreational drug. It is found naturally in the sap of the opium poppy, ''Papaver somniferum''. It is typically use ...

. For moderate pain, its effectiveness is roughly equivalent to that of codeine in low doses and

hydrocodone Hydrocodone, also known as dihydrocodeinone, is a semi-synthetic opioid used to treat pain and as a cough suppressant. It is taken by mouth. Typically, it is dispensed as the combination acetaminophen/hydrocodone or ibuprofen/hydrocodone fo ...

at very high doses. For severe pain, it is less effective than morphine. Pain-reducing effects last approximately six hours. The potency of analgesia varies considerably as it depends on an individual's genetics. People with specific variants of

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2 ...

enzymes may not produce adequate amounts of the active metabolite (desmetramadol) for effective pain control. Sleep medicine physicians sometimes prescribe tramadol (or other opioid medications) for

refractory In materials science, a refractory (or refractory material) is a material that is resistant to decomposition by heat or chemical attack and that retains its strength and rigidity at high temperatures. They are inorganic, non-metallic compound ...

restless legs syndrome Restless legs syndrome (RLS), also known as Willis–Ekbom disease (WED), is a neurological disorder, usually chronic, that causes an overwhelming urge to move one's legs. There is often an unpleasant feeling in the legs that improves temporaril ...

(RLS); that is, RLS that does not respond adequately to treatment with first-line medications such as

dopamine agonists A dopamine agonist is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like ...

(e.g.,

pramipexole Pramipexole, sold under the brand Mirapex among others, is a medication used to treat Parkinson's disease and restless legs syndrome. In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipexole is a ...

) or

gabapentinoid Gabapentinoids, also known as α2δ ligands, are a class of drugs that are chemically chemical derivative, derivatives of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA) (i.e., GABA analogues) which Voltage-dependent calcium cha ...

s, often due to augmentation.

Contraindications

Pregnancy and lactation

Use of tramadol during

pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

is generally avoided, as it may cause some reversible withdrawal effects in the newborn. A small prospective study in France found, while an increased risk of

miscarriage Miscarriage, also known in medical terms as a spontaneous abortion, is an end to pregnancy resulting in the loss and expulsion of an embryo or fetus from the womb before it can fetal viability, survive independently. Miscarriage before 6 weeks ...

s existed, no major malformations were reported in the newborn. Its use during

lactation Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The process ...

is also generally advised against, but a small trial found that infants breastfed by mothers taking tramadol were exposed to about 2.88% of the dose the mothers were taking. No evidence of this dose harming the newborn was seen.

Labor and delivery

Its use as an analgesic during labor is not advised due to its long onset of action (1 hour). The ratio of the mean concentration of the drug in the fetus compared to that of the mother when it is given intramuscularly for labor pains has been estimated to be 1:94.

Children

Its use in children is generally advised against, although it may be done under the supervision of a specialist. On 21 September 2015, the FDA started investigating the safety of tramadol in use in persons under the age of 17. The investigation was initiated because some of these people have experienced slowed or difficult breathing. The FDA lists age under 12 years old as a contraindication.

Elderly

The risk of opioid-related adverse effects such as

respiratory depression Hypoventilation (also known as respiratory depression) occurs when ventilation is inadequate (''hypo'' meaning "below") to perform needed respiratory gas exchange. By definition it causes an increased concentration of carbon dioxide (hypercapni ...

, falls, cognitive impairment, and sedation is increased. Tramadol may interact with other medications and increase the risk for adverse events.

Liver and kidney failure

The drug should be used with caution in those with liver or kidney failure, due to metabolism in the liver (to the active molecule desmetramadol) and elimination by the kidneys.

Side effects

The most common

adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. The term compli ...

s of tramadol include

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

dry mouth Xerostomia, also known as dry mouth, is a subjective complaint of dryness in the mouth, which may be associated with a change in the composition of saliva, reduced salivary flow, or have no identifiable cause. This symptom is very common and is o ...

indigestion Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier ...

, abdominal pain,

vertigo Vertigo is a condition in which a person has the sensation that they are moving, or that objects around them are moving, when they are not. Often it feels like a spinning or swaying movement. It may be associated with nausea, vomiting, perspira ...

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

, drowsiness, and

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

. Other side effects may result from interactions with other medications. Tramadol has the same dose-dependent adverse effects as morphine including respiratory depression. Side effects of Tramadol

Dependence and withdrawal

Long-term use of high doses of tramadol causes

physical dependence Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certa ...

and withdrawal syndrome. These include both symptoms typical of

opioid withdrawal Opioid withdrawal is a set of symptoms arising from the sudden cessation or reduction of opioids where previous usage has been heavy and prolonged. Signs and symptoms of withdrawal can include drug craving, anxiety, restless legs syndrome, naus ...

and those associated with

(SNRI) withdrawal; symptoms include numbness, tingling,

paresthesia Paresthesia is a sensation of the skin that may feel like numbness (''hypoesthesia''), tingling, pricking, chilling, or burning. It can be temporary or Chronic condition, chronic and has many possible underlying causes. Paresthesia is usually p ...

, and tinnitus. Psychiatric symptoms may include hallucinations, paranoia, extreme anxiety, panic attacks, and confusion. In most cases, tramadol withdrawal will set in 12–20 hours after the last dose, but this can vary. Tramadol withdrawal typically lasts longer than that of other opioids. Seven days or more of acute withdrawal symptoms can occur as opposed to typically 3 or 4 days for other codeine analogs.

Overdose

The clinical presentation in overdose cases can vary but typically includes neurological, cardiovascular, and gastrointestinal manifestations. The predominant neurological symptoms are

s and altered levels of consciousness, ranging from

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...

coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to Nociception, respond normally to Pain, painful stimuli, light, or sound, lacks a normal Circadian rhythm, sleep-wake cycle and does not initiate ...

. Seizures are particularly notable due to tramadol's lowering of the

seizure threshold The term seizure threshold is used to describe the balance between excitatory (glutaminergic) and inhibitory (GABA-ergic) forces in the brain which affect how susceptible a person is to seizures. Those diagnosed with epilepsy or certain other neuro ...

, occurring in approximately half of acute poisoning cases. Patients often exhibit

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...

and mild

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

. Gastrointestinal disturbances such as nausea and vomiting are common, and agitation, anxiety, and cold and clammy skin may also be present. While less common, severe complications like respiratory depression and

can occur, particularly in polydrug overdoses involving other CNS depressants (such as

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

s, opioids, and

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

) and agents with

serotonergic A serotonergic substance, medication, or receptor protein is one that affects neurotransmission pathways that involve serotonin, as follows: * Serotonergic drugs ** Serotonin receptor agonists ** Serotonin receptor antagonists ** Serotonin reupta ...

activity. Additionally, individuals with genetic variations leading to

enzyme duplication (rapid metabolizers) may have an increased risk of adverse effects, due to faster conversion of tramadol to its active

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

. Acute tramadol overdose is generally not life-threatening, with most fatalities resulting from polysubstance overdose. Management includes cardiovascular monitoring,

activated charcoal "Activated" is a song by English singer Cher Lloyd. It was released on 22 July 2016 through Vixen Records. The song was made available to stream exclusively on ''Rolling Stone'' a day before to release (on 21 July 2016). Background In an inter ...

administration, hydration, and treatment of seizures.

Naloxone Naloxone, sold under the brand name Narcan among others, is an opioid antagonist, a medication used to reverse or reduce the effects of opioids. For example, it is used to restore breathing after an opioid overdose. Effects begin within two ...

, an opioid antagonist, can partially reverse some effects of tramadol overdose, particularly respiratory depression. However, its use may increase the risk of seizures due to unopposed alpha-adrenergic stimulation. For suspected serotonin syndrome,

cyproheptadine Cyproheptadine, sold under the brand name Periactin among others, is a first-generation antihistamine, first-generation antihistamine with additional anticholinergic, antiserotonergic, and local anesthetic properties. It was patented in 1959 a ...

, a

serotonin antagonist A serotonin antagonist, or serotonin receptor antagonist, is a drug used to inhibit the action of serotonin and serotonergic drugs at serotonin (5-HT) receptors. Types 5-HT2A antagonists Antagonists of the 5-HT2A receptor are sometimes used ...

, is considered an effective antidote. The incidence of tramadol-related overdose deaths has been on the rise in certain regions. For instance, Northern Ireland has reported an increased frequency of such cases. In 2013, England and Wales recorded 254 tramadol-related deaths, while Florida reported 379 cases in 2011. In 2011, 21,649 emergency room visits in the United States were related to tramadol. The likely explanation for these observations is due to increase in frequency of prescriptions and use due to easier access due to lighter regulatory scheduling by authorities but this is starting to change. In 2021,

Health Canada Health Canada (HC; )Health Canada is the applied title under the Federal Identity Program; the legal title is Department of Health (). is the Structure of the Canadian federal government#Departments, with subsidiary units, department of the Gove ...

announced tramadol would be added to Schedule I of the

Controlled Drugs and Substances Act Control may refer to: Basic meanings Economics and business * Control (management), an element of management * Control, an element of management accounting * Comptroller (or controller), a senior financial officer in an organization * Controll ...

and to the Narcotic Control Regulations due to tramadol being suspected of having contributed to 18 reported deaths in Canada between 2006 and 2017.

Interactions

Tramadol capsules - 2022-09-22 - Andy Mabbett

Tramadol can have

pharmacodynamic Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...

pharmacokinetic Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific subs ...

, and pharmacogenetic interactions. Tramadol is metabolized by CYP2D6 enzymes which contributes to the metabolism of approximately 25% of all medications. Any medications with the ability to inhibit or induce these enzymes may interact with tramadol. These include common antiarrhythmics, antiemetics, antidepressants (

sertraline Sertraline, sold under the brand name Zoloft among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, generalized anxiety disorder, socia ...

paroxetine Paroxetine ( ), sold under the brand name Paxil among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used to treat major depressive disorder, obsessive-compulsive disorder, o ...

, and

fluoxetine Fluoxetine, sold under the brand name Prozac, among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used for the treatment of major depressive disorder, Anxiety disorder, anx ...

in particular), antipsychotics, analgesics, and tamoxifen. Due to tramadol's serotonergic effects, tramadol has the potential to contribute to the development of an acute or chronic hyper-serotonin state called

when used concurrently with other pro-serotonergic medications such as antidepressants (

SSRI Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by ...

s, SNRIs, tricyclics,

MAOIs Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, espec ...

antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...

triptan Triptans are a family of tryptamine-based medication, drugs used as abortive medication in the treatment of migraines and cluster headaches. This drug class was first commercially introduced in the 1990s. While effective at treating individual h ...

s, cold medications containing

dextromethorphan Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...

, and some herbal products such as

St. John's wort ''Hypericum perforatum'', commonly known as St. John's wort (sometimes perforate St. John's wort or common St. John's wort), is a flowering plant in the family Hypericaceae. It is a hairless, Perennial, perennial herb with woody Root, roots, y ...

. Concurrent use of

5-HT3 antagonist The 5-HT3 antagonists, informally known as "setrons", are a class of drugs that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain. With th ...

s such as

ondansetron Ondansetron, sold under the brand name Zofran among others, is a medication used to prevent nausea and vomiting caused by chemotherapy, radiation therapy, migraines, or surgery. It is also effective for treating gastroenteritis. It can be giv ...

dolasetron Dolasetron (trade name Anzemet) is a serotonin 5-HT3 receptor antagonist used to treat nausea and vomiting following chemotherapy. Its main effect is to reduce the activity of the vagus nerve, which is a nerve that activates the vomiting center i ...

, and

palonosetron Palonosetron, sold under the brand name Aloxi, is a medication used for the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV). It is a 5-HT3 antagonist. Palonosetron is administered intravenously, or as a single oral ...

may reduce the effectiveness of both drugs. Tramadol also acts as an opioid agonist and thus can increase the risk for side effects when used with other opioid and opioid-containing

s (such as

tapentadol Tapentadol, sold under the brand names Nucynta and Palexia among others, is a synthetic opioid analgesic with a dual mode of action as a highly selective full agonist of the μ-opioid receptor and as a norepinephrine reuptake inhibitor (NRI). T ...

oxycodone Oxycodone, sold under the brand name Roxicodone and OxyContin (which is the extended-release form) among others, is a semi-synthetic opioid used medically for the treatment of moderate to severe pain. It is highly addictive and is a commonly ...

fentanyl Fentanyl is a highly potent synthetic piperidine opioid primarily used as an analgesic (pain medication). It is 30 to 50 times more Potency (pharmacology), potent than heroin and 50 to 100 times more potent than morphine. Its primary Medici ...

, and

Tylenol 3 Codeine/paracetamol, also called codeine/acetaminophen and co-codamol, is a compound analgesic, comprising codeine phosphate and paracetamol (acetaminophen). Codeine/paracetamol is used for the relief of mild to moderate pain when paracetamo ...

). Tramadol increases the risk for seizures by lowering the seizure threshold. Using other medications that lower seizure threshold - such as antipsychotic medications,

bupropion Bupropion, formerly called amfebutamone, and sold under the brand name Wellbutrin among others, is an atypical antidepressant that is indicated in the treatment of major depressive disorder, seasonal affective disorder, and to support smo ...

(an anti-depressant and smoking cessation drug), and

amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...

s - can further increase this risk.

Pharmacology

Mechanism of action

Tramadol induces analgesic effects through a variety of different targets on the

noradrenergic system Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as a hormone, neurotransmitter and neuromodulator. The name "noradrenaline" (from Lat ...

, serotonergic system, and

opioid receptor Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostati ...

s system. Tramadol affects serotonin and norepinephrine reuptake inhibition similarly to certain antidepressants known as serotonin–norepinephrine reuptake inhibitors (SNRIs), such as

venlafaxine Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin–norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, pani ...

and

duloxetine Duloxetine, sold under the brand name Cymbalta among others, is a medication used to treat major depressive disorder, generalized anxiety disorder, obsessive–compulsive disorder, fibromyalgia, neuropathic pain, central sensitization, and ...

. Tramadol exists as a

racemic mixture In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...

, the positive

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

inhibits serotonin reuptake while the negative enantiomer inhibits noradrenaline re-uptake, by binding to and blocking the transporters. Both enantiomers of tramadol are agonists of the

and its M1 metabolite, O-

desmetramadol Desmetramadol (), also known as ''O''-desmethyltramadol (''O''-DSMT), is an opioid analgesic and the main active metabolite of tramadol. Tramadol is demethylated by the liver enzyme CYP2D6 to desmetramadol in the same way as codeine, and so sim ...

, is also a μ-opioid receptor agonist but is 6 times more potent than tramadol itself. All of these actions may work synergistically to induce analgesia. Tramadol has been found to possess these actions: *

Agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the

(MOR) and to a far lesser extent of the

δ-opioid receptor The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR or DOP, is an inhibitory 7-transmembrane G-protein coupled receptor coupled to the G protein Gi alpha subunit, Gi/G0 and has enkephalins as it ...

(DOR) and

κ-opioid receptor The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP for its ligand ketazocine, is a G protein-coupled receptor that in humans is encoded by the ''OPRK1'' gene. The KOR is coupled to the G protein Gi/G0 and is one of four re ...

(KOR) *

Serotonin reuptake inhibitor A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the drug action, action of the serotonin transporter (SERT). This in turn lea ...

(SRI) and

norepinephrine reuptake inhibitor A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinep ...

; hence, an SNRI *

Serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

5-HT_2C receptor

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.M₁ and M₃

muscarinic acetylcholine receptor Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several role ...

antagonist * α7

nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are Receptor (biochemistry), receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the c ...

antagonist *

NMDA receptor antagonist NMDA receptor antagonists are a class of drugs that work to receptor antagonist, antagonize, or inhibit the action of, the NMDA, ''N''-Methyl-D-aspartate receptor (NMDA receptor, NMDAR). They are commonly used as anesthetics for humans and anima ...

(very weak) *

TRPA1 Transient receptor potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1, TRPA1, or The Mustard and Wasabi Receptor, is a protein that in humans is encoded by the ''TRPA1'' (and in mice and rats by ...

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

Tramadol acts on the

s through its major

active metabolite An active metabolite, or pharmacologically active metabolite is a biologically active metabolite of a xenobiotic substance, such as a drug or environmental chemical. Active metabolites may produce therapeutic effects, as well as harmful effects. ...

, which has as much as 700-fold higher affinity for the MOR relative to tramadol. Moreover, tramadol itself has been found to possess no

efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as '' effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made betwee ...

in activating the MOR in functional activity assays, whereas desmetramadol activates the receptor with high intrinsic activity ( E_max equal to that of

). As such, desmetramadol is exclusively responsible for the opioid effects of tramadol. Both tramadol and desmetramadol have pronounced

selectivity Selectivity may refer to: Psychology and behaviour * Choice, making a selection among options * Discrimination, the ability to recognize differences * Socioemotional selectivity theory, in social psychology Engineering * Selectivity (radio), a ...

for the MOR over the DOR and KOR in terms of binding affinity. Tramadol is well-established as an SRI. In addition, a few studies have found that it also acts as a

serotonin releasing agent A serotonin releasing agent (SRA) is a type of drug that induces the release of serotonin into the neuronal synaptic cleft. A selective serotonin releasing agent (SSRA) is an SRA with less significant or no efficacy in producing neurotransmitter ...

(1–10 μM), similar in effect to

fenfluramine Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome. It was formerly used as an appetite suppressant in the treat ...

. The serotonin releasing effects of tramadol could be blocked by sufficiently high concentrations of the serotonin reuptake inhibitor 6-nitroquipazine, which is in accordance with other serotonin releasing agents such as fenfluramine and

MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (tablet form), and molly (crystal form), is an empathogen–entactogenic drug with stimulant and minor Psychedelic drug, psychedelic properties. In studies, it has been used ...

. However, two more recent studies failed to find a releasing effect of tramadol at respective concentrations up to 10 and 30 μM. In addition to serotonergic activity, tramadol is also a

. It is not a

norepinephrine releasing agent A norepinephrine releasing agent (NRA), also known as an adrenergic releasing agent, is a catecholaminergic type of drug that induces the release of norepinephrine (noradrenaline) and epinephrine (adrenaline) from the pre-synaptic neuron into ...

. Tramadol does not inhibit the reuptake or induce the release of

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

. A

positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...

imaging Imaging is the representation or reproduction of an object's form; especially a visual representation (i.e., the formation of an image). Imaging technology is the application of materials and methods to create, preserve, or duplicate images. ...

study found that single oral 50-mg and 100-mg doses of tramadol to human volunteers resulted in 34.7% and 50.2% respective mean occupation of the

serotonin transporter The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein t ...

(SERT) in the

thalamus The thalamus (: thalami; from Greek language, Greek Wikt:θάλαμος, θάλαμος, "chamber") is a large mass of gray matter on the lateral wall of the third ventricle forming the wikt:dorsal, dorsal part of the diencephalon (a division of ...

. The estimated median effective dose (ED₅₀) for SERT occupancy hence was 98.1 mg, which was associated with a plasma tramadol level of about 330 ng/mL (1,300 nM). The estimated maximum daily dosage of tramadol of 400 mg (100 mg ) would result in as much as 78.7% occupancy of the SERT (in association with a plasma concentration of 1,220 ng/mL or 4,632 nM). This is close to that of SSRIs, which occupy the SERT by 80% or more. Peak plasma concentrations during treatment with clinical dosages of tramadol have generally been found to be in the range of 70 to 592 ng/mL (266–2,250 nM) for tramadol and 55 to 143 ng/mL (221–573 nM) for desmetramadol. The highest levels of tramadol were observed with the maximum oral daily dosage of 400 mg per day divided into one 100-mg dose every 6 hours (i.e., four 100-mg doses evenly spaced out per day). Some accumulation of tramadol occurs with chronic administration; peak plasma levels with the maximum oral daily dosage (100 mg ) are about 16% higher and the area-under-the-curve levels 36% higher than following a single oral 100-mg dose.

Positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...

imaging studies have reportedly found that tramadol levels are at least four-fold higher in the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

than in plasma. Conversely, brain levels of desmetramadol "only slowly approach those in plasma". The

plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...

of tramadol is only 4–20%; hence, almost all tramadol in circulation is free, thus bioactive.

Correspondence to effects

Co-administration of

quinidine Quinidine is a class I antiarrhythmic agent, class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of Antimalarial medication, antimalarial agent quinine, originally derived from the bark of the cinchona tre ...

, a potent CYP2D6 enzyme inhibitor, with tramadol, a combination which results in markedly reduced levels of desmetramadol, was found not to significantly affect the analgesic effects of tramadol in human volunteers. However, other studies have found that the analgesic effects of tramadol are significantly decreased or even absent in CYP2D6 poor metabolizers. The analgesic effects of tramadol are only partially reversed by

naloxone Naloxone, sold under the brand name Narcan among others, is an opioid antagonist, a medication used to reverse or reduce the effects of opioids. For example, it is used to restore breathing after an opioid overdose. Effects begin within two ...

in human volunteers, hence indicating that its opioid action is unlikely the sole factor; tramadol's analgesic effects are also partially reversed by α₂-adrenergic receptor antagonists such as

yohimbine Yohimbine, also known as quebrachine, is an indole alkaloid derived from the bark of the African tree '' Pausinystalia johimbe'' (yohimbe); also from the bark of the unrelated South American tree '' Aspidosperma quebracho-blanco''. Yohimbine is ...

, the 5-HT₃ receptor antagonist

, and the 5-HT₇ receptor antagonists SB-269970 and SB-258719. Pharmacologically, tramadol is similar to

and

methadone Methadone, sold under the brand names Dolophine and Methadose among others, is a synthetic opioid used medically to treat chronic pain and opioid use disorder. Prescribed for daily use, the medicine relieves cravings and opioid withdrawal sym ...

in that it not only binds to the MOR, but also inhibits the reuptake of serotonin and norepinephrine due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity. Tramadol has inhibitory actions on the 5-HT_2C receptor. Antagonism of 5-HT_2C could be partially responsible for tramadol's reducing effect on depressive and obsessive–compulsive symptoms in patients with pain and co-morbid neurological illnesses. 5-HT_2C blockade may also account for its lowering of the

, as 5-HT_2C

knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death. However, the reduction of seizure threshold could be attributed to tramadol's putative inhibition of GABA_A receptors at high doses (significant inhibition at 100 μM). In addition, desmetramadol is a high-affinity ligand of the DOR, and activation of this receptor could be involved in tramadol's ability to provoke seizures in some individuals, as DOR agonists are well known for inducing seizures.

Nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

and

caused by tramadol are thought to be due to activation of the 5-HT₃ receptor via increased serotonin levels. In accordance, the 5-HT₃ receptor antagonist

can be used to treat tramadol-associated nausea and vomiting. Tramadol and desmetramadol themselves do not bind to the 5-HT₃ receptor.

Pharmacokinetics

Tramadol is metabolised in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

via the

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

isozyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. di ...

CYP2B6 Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances. Func ...

, and CYP3A4, being ''O''- and ''N''-demethylated to five different metabolites. Of these,

(''O''-desmethyltramadol) is the most significant, since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of 9 hours, compared with 6 hours for tramadol itself. As with codeine, in the 6% of the population who have reduced CYP2D6 activity (hence reducing metabolism), a reduced analgesic effect is seen. Those with decreased CYP2D6 activity require a dose increase of 30% to achieve the same degree of pain relief as those with a normal level of CYP2D6 activity. Phase II liver, hepatic metabolism renders the metabolites water-soluble, which are excreted by the kidneys. Thus, reduced doses may be used in renal and hepatic impairment. Its volume of distribution is around 306 L after oral administration and 203 L after parenteral administration.

Chemistry

Tramadol is marketed as a

of both ''R''- and ''S''-stereoisomers, because the two isomers complement each other's analgesic activities. The (+)-isomer is predominantly active as an opiate with a higher affinity for the μ-opiate receptor (20 times higher affinity than the (-)-isomer).

Synthesis and stereoisomerism

The chemical synthesis of tramadol is described in the literature.; since 2003 online with biannual actualizations. Tramadol has two stereogenic centers at the cyclohexane ring. Thus, may exist in ''four'' different configurational forms: * (1''R'',2''R'')-isomer * (1''S'',2''S'')-isomer * (1''R'',2''S'')-isomer * (1''S'',2''R'')-isomer The synthetic pathway leads to the racemate (1:1 mixture) of (1''R'',2''R'')-isomer and the (1''S'',2''S'')-isomer as the main products. Minor amounts of the racemic mixture of the (1''R'',2''S'')-isomer and the (1''S'',2''R'')-isomer are formed as well. The isolation of the (1''R'',2''R'')-isomer and the (1''S'',2''S'')-isomer from the diastereomeric minor racemate [(1''R'',2''S'')-isomer and (1''S'',2''R'')-isomer] is realized by the recrystallization of the hydrochlorides. The drug tramadol is a racemate of the hydrochlorides of the (1''R'',2''R'')-(+)- and the (1''S'',2''S'')-(−)-enantiomers. The resolution of the racemate [(1''R'',2''R'')-(+)-isomer / (1''S'',2''S'')-(−)-isomer] was described employing (''R'')-(−)- or (''S'')-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects of the (1''R'',2''R'')- and (1''S'',2''S'')-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals and in humans.

Detection in biological fluids

Tramadol and desmetramadol may be quantified in blood, plasma, serum, or saliva to monitor for abuse, confirm a diagnosis of poisoning or assist in the forensic investigation of a sudden death. Most commercial opiate immunoassay screening tests do not cross-react significantly with tramadol or its major metabolites, so chromatographic techniques must be used to detect and quantify these substances. The concentration of desmetramadol in the blood or plasma of a person who has taken tramadol is generally 10–20% that of the parent drug.

Discrepant reports on natural agency

In 2013, researchers Michel de Waard (then at Université Joseph Fourier, Grenoble, France, Grenoble and Grenoble Institute of Neuroscience, La Tronche) reported in ''Angewandte Chemie'' that tramadol was found in relatively high concentrations (>1%) in the roots of the African pin cushion tree, ''Nauclea latifolia'', concluding that it was a natural product in addition to its being a later human synthetic, and presenting a putative biosynthetic hypothesis for its origin. In 2014, Michael Spiteller (Technical University of Dortmund, Technische Universität Dortmund) and collaborators reported results, also in ''Angewandte Chemie'', that supported the conclusion that the presence of tramadol in those tree roots was the result of tramadol having been ingested by humans and having been administered to cattle (by farmers in the region); Spiteller et al. presented data that tramadol and its metabolites were present in animal excreta, which they then argue contaminated soil around the trees. They further observed that tramadol and its mammalian metabolites were found in tree roots in the far north of Cameroon where the commercial drug was in use, but not in the south where it was not being administered. A news report appearing in ''Lab Times'' at the time of the latter, 2014 paper, and reporting on its contents, also reported that Michel de Waard (communicating author of the original paper) continued to contest the notion that tramadol in tree roots was the result of anthropogenic contamination.Who Really did it First? Nature or a Pharmacist?
, in ''Lab Times online''; by Nicola Hunt; published 22 September 2014; retrieved 21 November 2015 The point was made that samples were taken from trees that grew in national parks, where livestock were forbidden, and it quoted de Waard extensively, who stated that "thousands and thousands of tramadol-treated cattle sitting around a single tree and urinating" would be required to produce the concentrations discovered. In 2016, Spiteller and colleagues followed up their preceding work with a carbon-14, radiocarbon analysis that supported their contention that the tramadol found in ''N. latifolia'' roots was of human synthetic origin rather being plant-derived.

Society and culture

Formulations

Available dosage forms include liquids, syrups, drops, elixirs, effervescent tablets, and powders for mixing with water, capsules, tablets including extended-release formulations, suppositories, compounding powder, and injections.

Patent history

The U.S. Food and Drug Administration (FDA) approved tramadol in March 1995, and an extended-release (ER) formulation in September 2005. ER Tramadol was protected by US patents nos. 6,254,887 and 7,074,430.FDA AccessData entry fo
Tramadol Hydrochloride
. Retrieved 17 August 2009. The FDA listed the patents' expiration as 10 May 2014. However, in August 2009, the US District Court for the District of Delaware ruled the patents invalid, a decision upheld the following year by the Court of Appeals for the Federal Circuit. Manufacture and distribution of generic equivalents of Ultram ER in the United States was therefore permitted before the expiration of the patents.

Legal status

Effective August 2014, tramadol has been placed into Controlled Substances Act#Schedule IV, Schedule IV of the federal Controlled Substances Act in the United States. Before that, some US states had already classified tramadol as a Schedule IV controlled substance under their respective state laws. Tramadol is classified in Schedule 4 (prescription only) in Australia, rather than as a Standard for the Uniform Scheduling of Drugs and Poisons#Schedule 8, Schedule 8 Controlled Drug (Possession without authority illegal) like most other

s. Effective May 2008, Sweden classified tramadol as a controlled substance in the same category as

and dextropropoxyphene, but allows a normal medical prescription, prescription to be used. In June 2014, the United Kingdom's Home Office classified tramadol as a Class C, Schedule 3 controlled drug, but exempted it from the safe custody requirement. In October 2023, New Zealand's Medsafe reclassified tramadol as a Class C2 Controlled Drug (in addition to its existing status as a prescription only medication).

Misuse

Illicit use of the drug is thought to be a major factor in the success of the Boko Haram terrorist organization. When used at higher doses, the drug "can produce similar effects to heroin." One former member said, "whenever we took tramadol, nothing mattered to us anymore except what we were sent to do because it made us very high and very bold, it was impossible to go on a mission without taking it." Tramadol is also used as a coping mechanism in the Gaza Strip under Gaza genocide, Israeli siege. It is also abused in the United Kingdom. From March 2019, the Union Cycliste Internationale (UCI) banned the drug, after riders were using the painkiller to improve their performance.

Research

Investigational uses

* Diabetic neuropathy * Antidepressant * Postherpetic neuralgia * Premature ejaculation * Adjunct to local anesthesia

Veterinary medicine

Tramadol was the most common opioid prescribed by American veterinarians from 2014 to 2019; however, usage has declined in subsequent years due to more recent evidence suggesting that dogs do not metabolise tramadol into O-desmethyltramadol effectively. As metabolisation of tramadol relies on

enzymes, it is species dependent and even individual genetics can have a profound impact on the efficacy of tramadol. A 2021 meta-analysis of tramadol use in dogs found that although tramadol was more effective than nalbuphine and

, it was less effective than

, COX inhibitors and multimodal analgesia with poor evidence to support the use of it is an analgesic for dogs. The mean alveolar concentration sparing effect of tramadol is negligible and with a high likelihood of rescue analgesia being required thus tramadol monotherapy is not recommended for the dog. One study looking at tramadol and meloxicam administered preoperatively provided no benefit compared to meloxican given alone. Another study looking at cimicoxib versus tramadol for long-term post-operative pain following a tibial-plateau-levelling osteotomy found that although the level of analgesia was similar cimicoxib resulted in better mobility and a lower incidence of hock (anatomy), hock oedema. These studies and other evidence suggest that non-steroidal anti-inflammatory drugs provide superior analgesia to tramadol in dogs. Tramadol is more effective in cats although oral tramadol is poorly tolerated leading to low compliance. A transdermal gel was formulated to address this but plasma concentrations were undetectable. In cats oral tramadol at 6 mg/kg provides equivalent analgesia to intramuscular tramadol at 4 mg/kg. One study comparing tramadol to meperidine found tramadol to be more effective at providing analgesia for cats undergoing ovariohysterectomy. A study looking at treatment of osteoarthritis in geriatric cats found owner-reported improvements but also significant adverse effects. Reported adverse effects of tramadol include: diarrhoea, dysphoria, anorexia (symptom), anorexia,

, pyrexia, tachypnoea, and increased levels of sertonin leading to agitation. Tramadol has the potential to cause

when administered alongside SSRI, serotonin re-uptake inhibitors, monoamine oxidase inhibitors, and tricyclic antidepressants. In horses tramadol is ineffective by itself. Two studies looking at intravenous tramadol found it provided no thermal or mechanical antinociception, another study looking at oral tramadol for chronic laminitis found it provided minimal analgesia, and another study looking at intraarticular tramadol found it provided no post-operative analgesia following arthroscopy; however, when administered with

(acetaminophen) tramadol provides short-acting mechanical antinociception and when administered with ketamine oral tramadol provides adequate analgesia for chronic laminitis. Based on this evidence tramadol is not recommended to be provided on its own for analgesia in horses.

Medical uses

Contraindications

Pregnancy and lactation

Labor and delivery

Children

Elderly

Liver and kidney failure

Side effects

Dependence and withdrawal

Overdose

Interactions

Pharmacology

Mechanism of action

Correspondence to effects

Pharmacokinetics

Chemistry

Synthesis and stereoisomerism

Detection in biological fluids

Discrepant reports on natural agency

Society and culture

Formulations

Patent history

Legal status

Misuse

Research

Investigational uses

Veterinary medicine

See also

References

Further reading