What is Tramadol?
- 1 What is Tramadol?
- 2 Tramadol Side Effects
- 3 Tramadol alternatives
- 4 Tramadol Withdrawal
- 5 Veterinary use of Tramadol
- 6 Tramadol Availability and Dosage
- 7 Tramadol Abuse and Detection
- 8 Tramadol Overdose
- 9 Tramadol Food Interactions
- 10 Tramadol Drug Interactions
- 10.1 Tramadol and Nonsteroidal Anti Inflammatory Drugs
- 10.2 Tramadol and Ibuprofen
- 10.3 Tramadol and Acetylsalicylic Acid
- 10.4 Tramadol and Celecoxib
- 10.5 Tramadol and Diclofenac
- 10.6 Tramadol and Naproxen
- 10.7 Tramadol and Carprofen
- 10.8 Tramadol and Indomethacin
- 10.9 Tramadol and Hypnotics (Zolpidem)
- 10.10 Tramadol and Antipsychotics (Aripiprazole)
- 10.11 Tramadol and Other Opioids
- 10.12 Tramadol an Acyclovir
- 10.13 Tramadol and Isotretinoin
- 10.14 Tramadol and First Generation Antihistamines
- 10.15 Tramadol and Buspirone
- 10.16 Tramadol and Tadalafil
- 10.17 Tramadol as Baclofen
- 10.18 Tramadol and Dayquil (Acetaminophen, Dextromethorphan, Doxylamine, Guaifenesin, Phenylephrine, Oxymetazoline)
- 10.19 Tramadol and Dicyclomine
- 10.20 Tramadol and Diazepam
- 10.21 Tramadol and Apixaban
- 10.22 Tramadol and Warfarin
- 10.23 Tramadol and Dexmethylphenidate
- 10.24 Tramadol and Prednisone
- 10.25 Tramadol and Norepinephrine and Serotonin Reuptake Inhibitors
- 10.26 Tramadol and Bupropion
- 10.27 Tramadol and Tricyclic Antidepressants
- 10.28 Tramadol and Sumatriptan
- 10.29 Tramadol and Butalbital
- 10.30 Tramadol and Acetaminophen, Butalbital and Caffeine (Fioricet)
- 10.31 Tramadol and Aspirin, Butalbital and Caffeine (Fiorinal)
- 10.32 Tramadol and Sulfamethoxazole/Trimethoprim
- 10.33 Tramadol and Clarithromycin
- 10.34 Tramadol and Cephalexin
- 10.35 Tramadol and Cefdinir
- 10.36 Tramadol and Metronidazole
- 10.37 Tramadol and Ciprofloxacin
- 10.38 Tramadol and Ledipasvir/Sofosbuvir
- 10.39 Tramadol and Valproate
- 10.40 Tramadol as Carbamazepine
- 10.41 Tramadol and Gabapentin
- 10.42 Tramadol and Levetiracetam
- 10.43 Tramadol and Clonazepam
- 10.44 Tramadol and St. John’s Wort
- 10.45 Tramadol and Garcinia Cambogia
Pain has become a public health issue, given that 1 out of every 5 adults experience it as an acute condition and for 1 out of every ten, it becomes a chronic problem.
Patients frequently complain about pain to both doctors and pharmacists, especially those over 65 years old, a rapidly growing demographic in the western world.
Concern over the importance of pain management lead to the creation of the OMS’ “3-Step Ladder” framework.
For situations corresponding to Step II in the “3-Step Ladder”, corresponding to moderate and/or persistent pain (lasting over 3 months) or in cases where no inflammation is present (rendering anti-inflammatory drugs useless), weak opioid drugs like tramadol (Ultram, Ultram ER, Conzip) become a good alternative.
Tramadol (IUPAC [(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride) acts upon the central nervous system, binding to the Mu, Sigma and Kappa receptors in a manner similar to endorphins (natural painkillers produced by the brain), while also reducing the reuptake of noradrenaline (allowing it to act longer in synapses) and the release of serotonin, both of which magnify the analgesic effect. Along with the central nervous system effect, the reduced reuptake of noradrenaline also contributes to a decrease in the conduction of pain signals, in the peripheral nervous system.
In order for Tramadol to be stable enough to be incorporated into pharmaceutical preparations, it is combined with hydrochloric acid, yielding Tramadol Hydrochloride as a racemic mixture of 1R,2R and 1S,2S enantiomers (compounds that have the same structure but as mirror images).
Tramadol acts both as a active drug and as a parent compound to a more effective hepatic metabolite M1(O-desmethyltramadol). This fact leads to greater variability in patient response to the drug, as metabolic polymorphisms in the relevant enzymes (CYP2D6 and CYP3A4), lead to varying degrees of conversion of Tramadol to O-desmethyltramadol (CYP2D6).
The recommended daily dosage for Tramadol is between 50 and 100 mg. Up to 6 daily doses may be taken, not exceeding 400 mg daily for immediate release and 300 mg daily for extended release formulations.
The onset of analgesic effect occurs 1 hour after taking the drug, with a maximum between 2 to 3 hours.
As with other centrally acting drugs, Tramadol also faces issues regarding tolerance (as the brain gradually compensates for the added stimulation of pain relieving neuronal pathways, reducing the drug’s effectiveness), leading to the need for a greater dosage and the accompanying increase in the likelihood of side effects (such as headaches, dizziness, drowsiness, tiredness and anxiety, as well as constipation, diarrhea, nausea, vomiting, and stomach pain).
Tramadol Side Effects
Side effect management and evaluation is important in any pharmacological therapy. In order to make the comparison between side effects and between the side effects of different drugs, these can be graded according to their severity.
- Mild: Grade I
- Temporary and mild discomfort
- Doesn’t limit patient’s activity
- Requires no medical intervention or therapy
- Moderate: Grade II
- Has a relatively small impact on daily activities
- Either requires no medical intervention or very limited intervention
- Severe: Grade III
- Daily activities are markedly impacted and assistance is usually necessary
- Medical intervention is usually necessary and may involve in-patient care
- Potentially Life Threatening: Grade IV
- Daily activity is extremely impaired and, significant assistance is required
- Medical intervention and monitoring is necessary, in a clinical setting.
The occurrence of side effects is often dose dependent and the following table shows the percentage of patients treated with tramadol, that experienced a given frequent side effect.
|Side effect||Grade||Incidence (%) of patients with adverse event by Tramadol dosage (mg)|
|Dizziness (not vertigo)||II||15.9||20.3||22.5|
Other side effects are rare (occurring in between 1 and 5 % of treated patients), and as such are harder to characterize, as far as dose dependency goes.
|Type of Disorder||Side effect||Grade|
|depression||II / III|
|Eye disorders||vision blurred||II|
|Gastrointestinal disorders||abdominal pain upper||II|
|Nervous system disorders||tremor||II|
|Metabolism and nutrition disorders||appetite decreased||II|
Others are rarer still, occurring in only between 0.5 and 1 % of patients.
|Type of Disorder||Side effect||Grade|
|Psychiatric disorders||euphoric mood||II / III|
|irritability/agitation||II / III|
|Decreased libido||II / III|
|sleep disorder/abnormal dreams||II / III|
|Aggravated constipation||II / III|
|Nervous system disorders||migraine||II / III|
|sedation||II / III|
|syncope||II / III|
|Vascular disorders||hypertension aggravated||III|
|andUrinary disorders||difficulty in micturition/ urinary retention||III|
Beyond these side effects, there are specific clinical conditions than can be triggered by Tramadol:
Although very rare, they are important because, in susceptible individuals, they can occur for usual therapeutic dosages (between 50 and 100 mg). However, 48% of patients experiencing seizures had other conditions, such as Head Trauma, Stroke or were being treated with medication, such as Tricyclic Antidepressants (like doxepin) or Serotonin and Noradrenalin Reuptake Inhibitor (like Cymbalta or Effexor) that increased risk.
In patients with a history of suicide attempts or suicidal ideation, the use of tramadol is suspected of increasing the risk of actual suicide. This association may not be causal, as patients with chronic pain (often treated with tramadol), are already at greater risk of suicide.
By interfering with the reuptake of Serotonin and having extensive hepatic metabolism, the use of Tramadol may lead to the development of Serotonin Syndrome. Tramadol may have an additive effect on Serotonin reuptake/availability, with other drugs being administered concomitantly (Selective Serotonin Reuptake Inhibitor (SSRIs), Serotonin and Noradrenalin Reuptake Inhibitor (NSRIs) and Monoamine Oxidase Inhibitors (MAOIs)), or may interfere with the metabolism of other drugs. This adverse reaction is rare with tramadol alone, but may reach an incidence as high as 14% with the riskier combinations.
Tramadol and Renal Failure
30% of Tramadol is excreted unchanged through the kidneys and its active metabolite also suffers renal excretion, thus any reduction of the renal function will increase the duration and intensity of the effects of Tramadol. In patients with renal failure the Tramadol dosage must be corrected to account for the slower clearance, but there are no other concerns, since Tramadol in not known to cause any kidney damage or impact renal function (unlike some NSAIDs, for instance). Patients with advanced Renal Failure should take no more than 50 mg per day (as the half-life of M1 can double, when compared to renal baseline patients).
Tramadol and Gastritis
Unlike other opioid drugs, Tramadol has very little effect on gastric motility and environment. The gastrointestinal effects of Tramadol are essentially derived from its central action and so, nausea and vomiting are not signs of any gastric aggression.
Tramadol may be a good alternative to NSAIDs in the pain management of patients with gastritis.
Patients experiencing severe and non-transient adverse reactions to Tramadol as well as those whose pain remains unmanaged (as is the case of patients developing tolerance or having inadequate metabolism of Tramadol to the more active M1 metabolite), may switch to alternative treatments.
One such alternative is Tapentadol (NUCYNTA®), which is very like Tramadol, but may be better tolerated by specific patients, although its side effects are basically the same as those of Tramadol, especially the risk of seizures and Serotonin Syndrome, to which severe hypotension may be added.
In cases where there is either loss or absence of efficacy it is possible for patients to move on to stronger opiates such as Hydromorphone (Dilaudid), Fentanyl (Durogesic) or Morphine (Ms Contin) or combinations of drugs like Hydrocodone/Acetaminophen (Norco), Oxycodone/Acetaminophen (Percocet).
When the Tramadol treatment must be discontinued due to the manifestation of side effects, and combination therapy (with lower Tramadol dosages) is not an option, clinicians may opt for drugs with entirely different structures and mechanism of action.
Gamma-Aminobutyric Acid analogues like Gabapentin (Neurontin, Gralise, Horizant) or Pregabalin (Lyrica) are especially good alternatives in cases of neuropathic pain (where pain stems from nerve damage).
Tricyclic Antidepressants and anticonvulsants like Carbamazepine (Tegretol) may also prove to be good alternatives to Tramadol.
When taken long enough and in high enough doses to produce habituation, a sudden stop in Tramadol therapy will produce withdrawal symptoms.
Being an opioid drug, Tramadol withdrawal symptoms are like those of other drugs in this family, initially (within 12 hours of the last dose):
- Muscle aches
- Increased tearing
- Runny nose
And as the detoxification process continues:
- Abdominal cramping
- Dilated pupils
- Goose bumps
Unfortunately, Tramadol is an atypical opioid, with significant impact in Serotonin and Noradrenalin regulation. This leads to symptoms like those seen in abrupt antidepressant (SSRIs and MAOIs) therapy discontinuation:
Treatment of severe Tramadol withdrawal makes use of traditional opioid addiction medication, such as Methadone and Buprenorphine. Both these drugs bind to the same receptors as Tramadol, but for much longer periods, reducing the psychological link between taking the drug and feeling good, while preventing withdrawal symptoms. The dosage for these treatments can then be gradually stepped down.
Depression or mood enhancing drugs (like Fluoxetine) can also be used, to ameliorate the withdrawal effects from the Serotoninergic and Noradrenergic effects of Tramadol.
The appropriate drugs can treat other specific withdrawal symptoms:
- For the nausea and vomiting, Metoclopramide (Reglan);
- For diarrhea, Loperamide (Imodium);
- For anxiety, Clonidine (Catapres);
Tramadol and Surgery
Tramadol is not usually used in preop, as it could have pharmacological or pharmacodynamic interactions with the drugs used in anesthesia. Tramadol is widely used in post op, for the management of moderate to severe pain, in cases where the use of a stronger painkiller is not necessary and/or recommended.
In major surgery (Hysterectomy), Tramadol has shown to have a better safety profile. Unlike with Morphine, the discontinuation of treatment with Tramadol produced no sensitization, since it is a weaker opioid and also operates via the serotoninergic pathways, with comparable efficacy.
For minor surgery, Tramadol may not be the best choice, as its effectiveness can easily be offset by the high incidence of side effects, most notably nausea. In cases when pain is not expected to be severe, Nonsteroidal anti-inflammatory drugs (NSAIDs) may be a better option.
Tramadol and Tattoos
As a centrally acting painkiller, Tramadol is effective at reducing the intensity of pain at any site, including the skin. In the context of tattoos, where the site is known in advance, a and NSAIDs afterwards would be the best choice, with better effectiveness and side effect profile. In case Tramadol is used, it should be taken 3 to 4 hours before the procedure, so that the time of maximum effect coincides with the procedure.
As with other use cases, Tramadol (or any other drug, for that matter) should not be taken without explicit indication from a doctor.
Tramadol and Pregnancy
Tramadol should be avoided during the first trimester of pregnancy (Category C) as there is an added risk of miscarriages, although this has not been extensively studied. In animal models, high doses of Tramadol have been shown to cause problems in organ development and bone growth.
Long term use of Tramadol during pregnancy may lead to Neonatal Abstinence Syndrome and/or seizures, as the neonate’s nervous system can also develop a tolerance/dependence to Tramadol.
Tramadol and Breastfeeding
Tramadol and its metabolites are present in human milk, corresponding to a dosage of about 3% the recommended infant dosage (a residual but significant dose), for mothers receiving a usual therapeutic dosage (up to 400 mg daily). This leads to a classification of Tramadol as not suitable for breastfeeding mothers. Following a single IV 100-mg dose of tramadol, the cumulative excretion in breast milk within sixteen hours post dose was 100 µg of Tramadol (0.1% of the maternal dose) and 27 µg of M1.
If lactation is not yet established, Tramadol’s effect on Prolactin may cause trouble in starting lactation, although it will have no effect on lactation if it is already underway.
In case Tramadol is taken by mistake this is not cause for suspending pregnancy. Tramadol is rapidly metabolized and for an accidental dosage (without buildup of both drug and metabolites in the blood, as is seen in continuous usage), peak concentration in milk will be negligible.
Veterinary use of Tramadol
As with humans, animals should only be given tramadol under explicit prescription by a doctor (veterinary).
In dogs and cats there seems to be less benefit in using Tramadol, as there is wide pharmacokinetic variability among individuals and side effect (like those seen in humans) are frequent. Due to a difference in feline and canine liver metabolism (when compared with humans), the more effective M1 metabolite cannot accumulate to effective levels, as it is rapidly metabolized to inactive metabolites, leaving the Tramadol parent compound as the sole responsible for pharmacological activity. The absence of M1 activity requires higher dosages of Tramadol for and effective therapy, making side effects that much more likely.
For dogs, the recommended maintenance dosage is 5 mg/kg every 6 hours and for cats 4 mg/kg every 6 hours.
In the case of dogs, proper analgesia may take up to 14 days to set in in earnest, for chronic conditions.
As with humans, treatment with tramadol is not recommended if the animal is already being treated with an SSRI like Fluoxetine or a Monoamine oxidase inhibitors (MAOI) like Selegiline, due to the additional risk of Serotoninergic Syndrome.
In case of overdose, treatment is mostly supportive as Naloxone (the opioid effect antagonist) increases the risk of seizures.
Tramadol Availability and Dosage
Tramadol is sold under the trademarks Ultram®, Tramal®, RyZolt®, Rybix®, ConZip® and several generic presentations.
For each brand name, there are also distinct formulations, corresponding to different drug effect.
Unlike with immediate release formulations, the management of forgotten doses should never involve phasing the schedule, as a predictable effect relies on stable conditions for the dissolution of the formulation. The missing dose should be taken as soon as possible and, if it is already too close to the following dose, it should just be omitted.
Oral release formulations like Ultram ODT®, disperse in the oral cavity in under 30 seconds, might lead to a speedier onset of effect (although there are no studies supporting this). The focus of these formulations is primarily ease of administration (since they don’t require water) and compliance, particularly in psychiatric patients (who may try to spit out regular tablets).
Since orally dispersible formulations are fragile, they should not be pushed out of their blister, but released by peeling away the blister cover. As they quickly dissolve in water, these pills should always be manipulated with dry hands. Ultram IR® and Tramal® 50 mg Capsules are Immediate Release formulations, claiming a release of 85% of the drug in under 90 minutes, with a fast onset of effect in under 1 hour.
A continuous painkilling regime may employ only immediate release formulations, but requires high frequency (from 4 to 6 hour intervals) that are not only cumbersome but are also more prone to the development of side effects, namely tolerance, addiction, and nausea (due to the pronounced spikes in serum levels of the drug).
Although no specific interactions with food are described, it is advisable that if the drug starts being taken with food, it should continue to be so, throughout the treatment, and likewise, if taken without food, it should always be taken without food. This stems from the high rate of hepatic metabolism of Tramadol, as certain foods may lead to an activation or inhibition of the hepatic enzymes responsible for metabolizing Tramadol, with unpredictable impact on the serum levels of active metabolites.
In case of a forgotten dose, it should be taken as soon as possible and the schedule phased (with the following administrations having a delay equal to the one that has occurred), to maintain the same intervals. If phasing the dosage regimen is not desirable (because of sleep schedules, meal times or administration of other drugs), a dose may be omitted or the schedule may simply continue unaffected (as the drug metabolism is fast and the increase in serum levels due to overlap of dosages will be of short duration.
The extended formulations like Ultram ER® (and also Ryzolt® and Conzip® 200 and 300 mg), have a dissolution time of between 12 and 15 hours, allowing a single daily dose (that would produce unacceptable side effects were it immediately released). Unlike with immediate release formulations, where the integrity of the pill or capsule is irrelevant, for extended release formulation, it is extremely important that there is no damage (such as cutting pills in half, or crushing them), since the controlled release hinges on the integrity of semi-permeable membranes or on a specific surface area of a drug holding matrix (depending on the formulation). Damage to a controlled release pill or capsule leads to faster release, with added risk for side effects (and even toxicity) and lower duration of pain-killing.
Tramadol Abuse and Detection
Drug testing is important as a promoter of workplace safety and medication compliance, as well as in the prevention of abuse and/or diversion and in a forensic context.
Tramadol is a Schedule IV synthetic Codeine analog, having a relatively low, but nevertheless present, potential for abuse.
Most of the abusers tend to be over 25 and with an history of substance abuse, but also healthcare professionals (due to easy access to the drug).
At sufficiently high dosages, it can produce an euphoric “high”, similar to that of other opiates, and lower but sustained doses lead to an improvement in mood (similar to that of some antidepressants), which may also lead to abuse via psychological dependency.
Another reason for abuse is the occurrence of withdrawal symptoms, which can be alleviated by resuming the therapy:
- Gastrointestinal pain
All the above-mentioned reasons, coupled with a relative ease in procuring the drug, make it susceptible to non-medical use.
The prevention of abuse hinges both in the patient’s attitude and the doctor’s vigilance. Patients should never exceed the 400-mg maximum daily dosage, to delay the onset of tolerance and the accompanying potential for withdrawal symptoms. Individual doses should also not exceed 100 mg, in order to avoid the onset of euphoria (not to mention potential overdose).
Doctors should restrict treatment to the minimum time required for symptom resolution. In case the patient’s response is inadequate, stronger medication should be used, to avoid potential overuse.
Unlike Schedule I and II drugs, standard drug tests do not detect Tramadol, requiring either a specific test (like the NarcoCheck® Tramadol Test) or specialized equipment such as gas chromatography, mass spectrometry, or High Performance Liquid Chromatography (HPLC)
Tramadol can be detected in blood, urine, and saliva, as well as in hair, with clean up periods of variable length, depending on the method, with urine samples being the most commonly used.
In urine, tramadol and/or its metabolites can be detected between 1 and 3 days after the last use, although increased water intake or body fat content can affect this. In cases where there is suspicion of tampering with the sample, a blood (up to 3 days) or saliva (12 to 36 hours) test can be used.
Longer term detection requires the use of hair samples, where use can be detected between 14 and 90 days after the last use.
Tramadol overdose occurs mostly due to abuse, but can also occur in individuals with either increased hepatic metabolism (either physiologic or due to liver enzyme induction) or reduced excretion, leading to a buildup of the M1 metabolite.
Tramadol overdose may be fatal as the accompanying central respiratory depression may impair self-life support. Although toxicity onset and escalation is fast, it helpful to be aware of the early signs of overdose, as a timely medical intervention can prevent fatal or permanently debilitating outcomes.
A Tramadol overdose initially manifest by:
- Contracted pupils
- Extreme drowsiness
- Slowed breathing
- Slowed heartbeat
- Weak muscles
Eventually leading to loss of consciousness.
These symptoms require immediate medical attention, which will focus on establishing adequate Oxygen pressure until the patient can breathe on his own.
In extreme cases Naloxone (an opioid receptor antagonist) can be used, although the reversal of symptoms will only be partial (as Tramadol not only acts on the mu opioid receptor, but also on the Serotonin and Noradrenalin reuptake), with Naloxone adding to the risk of seizures.
The prevention of overdose requires the collaboration of patients and doctors.
For doctors it is important to monitor inpatient respiratory function, remembering that even though Tramadol is a weak opioid, there may be genetic variability and/or other situations making a patient more susceptible to overdose. For out-patients, doctors should make sure that the medication is effective (avoiding patient self-overmedication) and that refill prescriptions follow what would be expected for the prescribed dosage.
Patients should always follow the prescription to the letter, reporting any lack of efficacy, rather than autonomously raising the dosage. Patients should also keep their medication safe and out of the reach of potential recreational users. It is also important not to mix central nervous system depressants (such as alcohol, sleeping pills, etc.) as they can lower the toxicity threshold for Tramadol. A Tramadol overdose may also prevent with life threatening symptoms other than respiratory depression, such as pulmonary edema, cardiac arrest, and hepatic failure, all requiring specialized management, stressing the importance of medical intervention.
Tramadol Food Interactions
Tramadol and Ethanol(Alcohol)
Can I drink alcohol with tramadol? Ethanol consumption should be avoided while taking Tramadol. Ethanol increases the expression of the CYP3A4 enzyme and increases its activity, leading to accelerated metabolism of Tramadol to its less active form (metabolite M2) and therefore a weaker effect. Not only this, but ethanol is also a central nervous system depressant, an effect that adds to Tramadol’s own depressive action, increasing somnolence and the risk for respiratory depression.
For patients with moderate ethanol consumption, Tramadol may be expected to have baseline effect after one hour per each 10ml of pure ethanol (1:45 after a shot of vodka). For patients who regularly abuse ethanol, there will be a significantly higher amount of CYP3A4 enzymes in their liver and it will take up to six days for their level to reach baseline, after the last time ethanol is consumed.
For patients taking Tramadol formulations with immediate release, ethanol may be consumed in little over 8 hours without risk of additive central nervous system depression. For patients taking tramadol in delayed release formulations, ethanol can only be consumed without risk of central nervous system depression after 24 hours.
Tramadol and Caffeine
Can I drink coffee with tramadol? Caffeine is metabolized in an entirely different enzyme system from Tramadol and so there is little risk of pharmacodynamic interactions between these two substances. Caffeine is also a stimulant of the central nervous system, interacting with entirely different receptors from those affected by Tramadol, and as such also poses no risk of either increasing or decreasing the activity of the drug.
In animals, there is some evidence that caffeine may even have a synergistic analgesic effect with Tramadol, but this has not been corroborated by human studies.
Tramadol and Grapefruit juice
Grapefruit juice contains furanocoumarins which are potent and irreversible inhibitors of the CYP3A4 and CYP2D6 enzymes. Since Tramadol is, by itself, a moderately active painkiller, relying on hepatic metabolism for conversion into its much more active metabolite M1, the inhibition of its main metabolizing enzyme families leads to marked decrease in effectiveness. On the other hand, there will be an accumulation of Tramadol itself, which can lead to an increase of side effects.
This effect can persist for up to 72 hours after grapefruit juice is ingested, making this a particularly troublesome interaction, as the loss of effect may lead patients to self-medicate with higher doses, risking the side effects that are caused by Tramadol itself (serotoninergic effects).
Tramadol and Orange Juice
Orange juice has no central nervous system effect and does not induce or inhibit the enzyme families responsible for metabolizing Tramadol and as such, it is perfectly safe to drink orange juice while taking tramadol.
Tramadol Drug Interactions
Tramadol and Nonsteroidal Anti Inflammatory Drugs
The OMS’ “3-StepLadder” framework for pain management, places the use of non-opioid painkillers, such as Paracetamol and Nonsteroidal Anti Inflammatory Drugs (NSAIDs) like Ibuprofen (Advil, Nurofen, Motrin) as the first line choice in pain management.
NSAIDs work by inhibiting cyclooxygenase isoenzymes (COX-1 and COX-2), involved in the production of inflammation promoting substances like prostaglandins. The actual therapeutic effect comes from the inhibition of COX-2, which is activated at the sites of inflammation, while the inhibition of COX-1 is primarily associated with side effects such as gastric bleeding/ulceration (since the prostaglandins produced via COX-1 are essential to the secretion of the gastric lining’s protective layer). As prostaglandins are also involved in the regulation of blood flow, NSAIDs also have both renal and cardiovascular side effects, as blood flow may be reduced, leading to lower renal perfusion and higher vascular.
Although these therapies are widely used and have an excellent short term safety profile, issues regarding both efficacy (when managing stronger pain) and long term safety (gastric inflammation, renal damage, hypertension, and heart failure), have led to research into superior alternatives.
Using Tramadol in Combination with NSAIDs provides, not only synergistic (for most combinations) painkilling effect (with the effect of taking both drugs being greater that what would be expected by simply adding their individual contribution), but also and due to this a better safety profile (with less frequent and milder side effects), by allowing the use of lower dosages.
This is particularly true for instances where long term pain is associated with inflammation, such as with rheumatoid arthritis.
Although this type of combination of drugs leads to outstanding painkilling performance, the scientific literature places emphasis on safety gains.
Tramadol and Ibuprofen
In the case of Ibuprofen associated with Tramadol doses can become as lower than 600 and 400 mg/day respectively (insufficient by themselves in cases of moderate pain), hemorrhages and gastric bleeding, as well as tolerance are greatly reduced.
Unfortunately, this combined therapy is not without problems…
In children under 17 years of age, the use of Tramadol poses an increased risk of respiratory depression (as, like other centrally acting drugs, it reduces the breathing reflex), making it the limiting factor in the use of this therapy, making it a contra-indication. Nevertheless, it has seen off-label use in a post-op context (like in tonsillectomies), patients must be carefully monitored, as differences in metabolism may lead to a buildup of the drug in the brain, leading to a rapid onset of severe respiratory depression.
In patients, older than 65 years of age, the side effects of Ibuprofen take precedence in limiting this combination’s usefulness, as every year above 65 can add up to 4% extra risk of renal and gastric toxicity.
Tramadol and Acetylsalicylic Acid
In alleviating postoperative pain Tramadol, has been associated with Acetylsalicylic Acid (the active drug in Aspirin) in Patient Controlled Analgesia, leading to a reduced dosage of Tramadol and a corresponding lowering of reported side effects (namely nausea and sedation). Unfortunately, the combined effect seems to be purely additive unlike other combinations.
Tramadol and Celecoxib
Tramadol has been used in association with Celecoxib (Celebrex), in patients with osteoarthritis. Studies have shown that, as with other NSAIDs, there was a marked improvement in pain management efficacy (41.5 in combination vs 48.3 for celecoxib alone, in the visual analog pain scale), with a Tramadol dose of 154 mg per day.
Celecoxib is a selective COX-2 inhibitor and as such has no impact on the physiological role of prostaglandins, avoiding most of the side effects typically associated with NSAIDs. The most common treatment-related adverse events were somnolence (6.5%), nausea (4.6%), and constipation (3.3%), all attributable to Tramadol.
Tramadol and Diclofenac
Diclofenac has been used in association with Tramadol in a post-op setting (Post hysterectomy). Unfortunately, there seemed to be no benefit for this combination in pain management.
Tramadol and Naproxen
In osteoarthritis patients, the association of Tramadol (200 mg per day) allowed the Naproxen (Aleve) dosage to be significantly reduced, without any loss in effectiveness, from 1000 to as low as 200 mg per day.
For this combination, side effects are dominated by Tramadol, namely nausea and somnolence, as the dosage for Naproxen fell below what would be necessary for its side effects to manifest significantly.
Tramadol and Carprofen
Carprofen is a veterinary drug only and should not be used by humans (although human use was discontinued solely on commercial grounds). In dogs, it behaves as a COX-2 specific inhibitor. As with Celecoxib the association allows for lower dosages of both drugs and thus lower risk for side effects.
Tramadol and Indomethacin
Indomethacin has been used with Tramadol (Tramal Retard) in the treatment of severe osteoarthritic pain, with excellent results when compared with Indomethacin alone. There was a sight decrease in bowel movements, but much smaller than what would have been expected with other opioid drugs.
There was also an improvement in the quality of sleep, as the unmanaged pain made it difficult for patients to sleep. The introduction of Tramadol not only reduced patient discomfort but also introduced light sedation/monoaminergic effect (like SSRIs), making it easier for them to fall asleep (although this can also be considered a drawback for patients that have issues with somnolence), particularly on the beginning of the treatment.
Combined therapy with Tramadol and NSAIDs is problematic in patients with preexisting conditions such as renal, heart or liver failure, although it is not absolutely disallowed, requiring only lower dosages (with tramadol going as low as 50 mg twice daily), more careful monitoring and shorter treatments.
By placing added load on the liver function, Tramadol increases the risk of hepatic encephalopathy in patients with liver failure. In these patients, the reduced hepatic function can also lead to a buildup of the drug, increasing the development of tolerance.
In patients with renal failure, the safety issues raised by NSAIDs are compounded by an increase in respiratory depression (as both Tramadol and its byproducts are removed less efficiently from the blood stream) and the possible onset of serotoninergic syndrome (with changes in mood, and disturbances in the autonomous nervous system).
In patients with heart failure, NSAIDs are, once again, the limiting factor. Their effect on blood flow regulation leads to increased cardiovascular stress (higher blood pressure and/or reduced flow), exacerbating the condition.
Tramadol and Hypnotics (Zolpidem)
Zolpidem is a short acting nonbenzodiazepine hypnotic (Alfa-1 Gamma-Aminobutyric Acid Agonist). There have been no specific studies about the association of Tramadol with Hypnotics like Zolpidem (Ambien). Theoretically this combination should be avoided as the sedation caused by the hypnotic will have a cumulative effect with Tramadol, leading to a degradation of cognitive and motor functions, especially in women. Furthermore, since they are both metabolized by the same liver enzyme system, Tramadol may decrease the rate at which Zolpidem is metabolized, thus increasing its effect, while having a lower effect itself.
Tramadol and Antipsychotics (Aripiprazole)
There have been no specific studies about the association of Tramadol with Aripiprazole (Abilify). Since both drugs are metabolized by the CYP3A4 enzyme in the liver, it is possible for a pharmacodynamic interaction to develop, as the production of M2 is reduced, in favour or the more active M1 Tramadol metabolite (increasing its pain killing effect) and less Aripiprazole is cleared (increasing its permanence in the bloodstream and thus its effect), as both molecules compete for the same metabolic pathway.
Tramadol and Other Opioids
There is no reason for tramadol to be used together with other opioids such as Buprenorphine (Suboxone, Butrans), Hydromorphone (Dilaudid) and Hydrocodone. The receptors which Tramadol acts upon are the same that are acted upon by other opioids, but with the later having stronger affinities. Using Tramadol with other opioids would only serve to reduce their efficacy (as they compete for the same receptors) and increase the likeliness of side effects.
Tramadol an Acyclovir
There are no reported interactions between Acyclovir and Tramadol. Acyclovir is primarily eliminated by renal excretion and its liver metabolism does not use the same enzyme families as Tramadol, making this combination perfectly safe from a pharmacodynamic perspective.
Tramadol and Isotretinoin
Isotretinoin is used in the treatment of severe acne. Although there are no reported interactions between Isotretinoin (Accutane) and Tramadol, both these drugs suffer extensive metabolism by the CYP3A4 liver enzyme and, as such, there is potential for both substances to compete, leading to higher effect of Tramadol as a painkiller (since the more active metabolite M1 is produced by CYP2D6) and accumulation of isotretinoin.
Tramadol and First Generation Antihistamines
First generation antihistamines are inverse agonist (making histamine work in reverse on its receptors) on both peripheral and central nervous system H1 receptors, used in the treatment of allergic reactions and as a sedative.
Diphenhydramine (Benadryl) and Hydroxyzine (Atarax) should not be taken together with Tramadol as they have a high potential for interactions. The central H1 inverse agonism leads to somnolence, which adds to the effect already caused by Tramadol. These drugs are also Serotonin Reuptake inhibitors like Tramadol, increasing the risk of Serotonin syndrome. Finally, both Diphenhydramine and Hydroxyzine are inhibitors of CYP2D6, reducing the production of the M1 metabolite and thus severely diminishing Tramadol’s analgesic activity, (which can last for several hours).
Tramadol and Buspirone
Buspirone is used in the treatment of anxiety disorders. Buspirone should not be used together with Tramadol. Buspirone interaction with Tramadol is both pharmacological and pharmacodynamic. On one hand Buspirone has an overall noradrenergic effect, which can add Tramadol’s own noradrenaline increase. On the other hand, Buspirone is also metabolised by the CYP3A4 enzyme, raising the possibility of competitive inhibition of this enzyme, leading to a higher effect of Tramadol and higher of Buspirone.
Tramadol and Tadalafil
Tadalafil (Cialis) is a phosphodiesterase-5 inhibitor, used in the treatment of erectile dysfunction and, in patients suffering from concomitant premature ejaculation, Tramadol has been used as an ejaculation retardant. Unfortunately, the combined use of these drugs has been shown to cause a significant alteration in liver functions evidenced by an increase in the serum concentration of liver enzymes and bilirubin, and a decrease in the conjugation percentage of serum bilirubin. Furthermore, both drugs are metabolized by the CYP3A4 enzyme, which may lead to competition between both substrates, leading to a higher effect of tramadol and higher effect of tadalafil.
Tramadol as Baclofen
Baclofen is used as a spasmolytic and muscle relaxer but also as a co-analgesic in combination with other painkilling drugs. In mice, Baclofen has a synergistic painkilling with Tramadol, making smaller dosages much more effective, via simultaneous effect on opioid and gamma-aminobutyric acid (GABA) receptors. Furthermore, because Baclofen also interferes with the GABA-B receptor, in the emetic control pathway, then Tramadol induced nausea and vomiting are also reduced.
There have been no specific studies about this association, but as both drugs cause somnolence, this side effect can be aggravated.
Tramadol and Dayquil (Acetaminophen, Dextromethorphan, Doxylamine, Guaifenesin, Phenylephrine, Oxymetazoline)
Dayquil is a combination of drugs used in the treatment of pain, nasal congestion and cough associated with colds and the flu. Due to its complex composition, it has a greater risk of interaction, as more drugs compete for metabolic pathways and pharmacological effects superimpose.
It is safe to associate Tramadol with Acetaminophen as the two provide complementary analgesic action and although Acetaminophen is also metabolized via the CYP3A4 enzyme, it is only marginally so (as its primary metabolic pathway is via glucuronidation), there are several formulations containing both these drugs.
Dextromethorphan has serious potential for interaction with Tramadol. Dextromethorphan acts upon the opioid receptors in a similar way to Tramadol (hence its effect as a cough suppressant) and the combination of the two may lead to increased sedation and respiratory depression. Dextromethorphan has serotoninergic and noradrenergic effect and as such, when combined with Tramadol, raises the risk of Serotonin Syndrome.
Doxylamine is a first-generation antihistamine and as such readily crosses the brain-blood barrier, causing somnolence, which can be magnified when used together with Tramadol.
Guaifenesin helps thin out secretions in the respiratory tract but it also has activity on the central nervous system, also acting as a muscle relaxant and anticonvulsant. Guaifenesin can cause nausea, increasing the risk for this side effect when combined with Tramadol. Guaifenesin may also potentiate Tramadol’s sedative effect leading to increased somnolence.
Phenylephrine is a selective α1-adrenergic receptor agonist used primarily as a decongestant. It is unlikely that it has any interaction with Tramadol since neither action nor metabolism have any superposition between them.
Oxymetazoline is like Phenylephrine but it also has effect on the α2-adrenergic receptor. Since it can interact with central α2-adrenergic and imidazoline receptors, it can potentiate Tramadol’s central nervous system depression.
Tramadol and Dicyclomine
Dicyclomine (Bentyl) is used as a smooth muscle relaxant, to relieve muscle spasms in the gastrointestinal tract. Due to its anticholinergic action, it can increase the likelihood of nausea and somnolence, when taken together with Tramadol, as these are common side effect for both drugs.
Tramadol and Diazepam
Diazepam (Valium)is a benzodiazepine used as an anxiolytic and muscle relaxant. As both drugs are central nervous system depressants, this effect may be compounded when both are taken together, leading to increased incidence of somnolence and dizziness. Diazepam is also metabolized by CYP3A4 which may lead to pharmacodynamic interaction as both drugs may compete in metabolism, leading to an increased effect of Tramadol.
Tramadol and Apixaban
Apixaban (Eliquis) is a selective inhibitor of Blood Coagulation Factor Xa (FXa) used as a blood thinner. Both Apixaban and Tramadol can cause nausea and as such, using these two drugs can increase the risk for this side effect. Apixaban is extensively metabolized by the CYP3A4 enzyme thus there is a possibility for competition of both substances for the same enzyme system, increasing the effectiveness of Tramadol. Despite this potential for interaction, this combination may be safer for patients requiring pain and coagulation management, as NSAIDs (which would be the natural stage I choice) are known to have severe interactions with Apixaban (especially Naproxen).
Tramadol and Warfarin
Warfarin (Coumadin) is an inhibitor of vitamin K epoxide reductase, greatly increasing the loss of active vitamin K which is essential for coagulation, thus acting as a potent and long lasting blood thinner. There are contradictory studies regarding the effect of tramadol on the metabolism of warfarin and its subsequent effect (as measured by change in International Normalized Ratio (INR)). Since both drugs are metabolized by CYP3A4 there is a possibility for competitive inhibition of the metabolism of warfarin, which is of particular concern taking into account warfarin’s long half-life and long duration of effect (any slight decrease in its metabolism can lead to dangerous accumulation of the drug), especially in patients exhibiting lower activities in the CYP2D6 enzyme. As with Apixaban, this is still a better drug combination for patients requiring pain management than NSAIDs and if an interaction is detected, the Warfarin dosage can simply be adjusted, making concurrent use with Tramadol viable.
Tramadol and Dexmethylphenidate
Dexmethylphenidate (Focalin) is central nervous system stimulant by inhibiting the reuptake of Dopamine, Serotonin and Noradrenaline, used in the management of Attention Deficit Hyperactivity Disorder (ADHD). As a inhibitor of serotonin and noradrenalin reuptake, Dexmethylphenidate increases the risk of Serotonin Syndrome when taken together with Tramadol. Dexmethylphenidate is also metabolized by the CYP2D6 enzyme, raising the possibility of competitive inhibition and thus decreased action by Tramadol.
Tramadol and Prednisone
Prednisone (Deltasone, Rayos, Sterapred, Meticorten) is a synthetic glucocorticoid, used in the treatment of inflammatory conditions such as Rheumatoid Arthritis, Crohn’s Disease, and other like Chronic Obstructive Pulmonary Disease and Lupus.
Prednisone is inactive by itself but, after being metabolized in the liver (through the CYP3A4 enzyme), its metabolites become biologically active, leading to:
- Reduction in Edema
- Reduction of the release of proinflammatory mediators (such as Prostaglandins)
- Reduction in the overall Immune Response
In combination with tramadol, Prednisone plays a complementary role, by eliminating an eventual inflammatory cause for pain, while Tramadol directly acts on it, especially since there are no documented interactions between the two drugs. Unlike with other anti-inflammatory drugs, Prednisone has no deleterious effect on renal function.
The use of this association is primarily limited by the side effects of prednisone, particularly immune suppression and increase in blood sugar.
Tramadol and Norepinephrine and Serotonin Reuptake Inhibitors
Norepinephrine Serotonin Reuptake Inhibitors and Serotonin Specific Reuptake Inhibitors are used as antidepressants and mood regulators.
Duloxetine (Cymbalta) is a powerful NSRI, while also inhibiting Dopamine reuptake to a lesser degree. It is a first line treatment for major depressive disorders and in Diabetic Neuropathic Pain. Both Tramadol and Duloxetine inhibit the reuptake of Serotonin and Norepinephrine, leading to a buildup of these neurotransmitters in synapses. Duloxetine is an inhibitor of CYP2D6, which leads to a buildup of Tramadol (with more Serotoninergic effect) and a decrease of the M1 metabolite (with more opioid effect), further increasing the risk of Serotonin Syndrome. Furthermore, due to its excitatory properties, Duloxetine may increase the risk of seizures when combined with Tramadol.
Venlafaxine is very like Duloxetine in both action and interaction with Tramadol, although with higher risk. Venlafaxine inhibits both CYP2D6 and CYP3A4, leading to a greater buildup of Tramadol (since both its main metabolizing enzymes are inhibited) and thus greater Serotoninergic effect, increasing the risk of Serotonin Syndrome. Venlafaxine is also associated with suicidal ideation which is also reported for Tramadol, increasing the risk of suicide for patients taking both drugs.
Nevertheless, there is no absolute contraindication for treatment with Tramadol and NSRIs, if the dosage for both drugs is kept low and there is adequate medical oversight, with appropriate intervention at the first signs of Serotonin Syndrome.
Citalopram (Celexa) and Escitalopram (Lexapro) are SSRIs and as such, by their pharmacological action, increase the risk of Serotonin Syndrome, when taken together with Tramadol. Both Citalopram and Escitalopram are inhibitors of the CYP2D6 enzyme, limiting the amount of M1 produced (reducing the opioid effect), leading to a buildup of Tramadol (increasing the serotoninergic effect), magnifying the risk of Serotonin Syndrome.
Tramadol and Bupropion
Bupropion is a substituted cathinone that inhibits the reuptake of Norepinephrine and Dopamine, used as an antidepressant and in smoking cessation. Bupropion is an inhibitor of the CYP2D6 enzyme, limiting the amount of M1 produced (reducing the opioid effect), leading to a buildup of Tramadol (increasing the serotoninergic effect). Due to its excitatory action, Bupropion, when combined with Tramadol, may increase the risk of seizures. Bupropion is also (although rarely) been associated with an increase in suicidal ideation and together with Tramadol, may increase the risk of suicide.
Tramadol and Tricyclic Antidepressants
Tricyclic Antidepressants like Doxepin (Silenor, Zonalon) or Amitriptyline (Elavir) are used in the treatment of anxiety and sleep disorders as well as depression, chronic pain. They can also be used as migraine prophylactics. Tricyclic Antidepressants are Serotonin and Norepinephrine Reuptake Inhibitors and as such can potentiate the risk of Serotonin Syndrome and also seizures, due to their excitatory effect. There is also a potential for a pharmacodynamic interaction, as Tricyclic Antidepressants are inhibitor of the CYP2D6 enzymes, leading to a decrease of the M1 metabolite and an accumulation of Tramadol, reducing the opioid effect but increasing the serotoninergic. The risk of this association significantly depends on the degree of Serotonergic action of the specific drug. Amitriptyline, with the lowest degree of Serotonin Reuptake inhibition is thus the safest in combination with Tramadol.
Tramadol and Sumatriptan
Sumatriptan (Imitrex) is a 5-HT1D and 5-HT1B Serotonin receptor agonist, used for the treatment of migraine (as its target receptors are mostly prevalent in the cranial arteries and veins, where it reduces migraine inducing inflammation). While this drug is most active in vascular serotoninergic receptors, its specificity is not absolute and so the risk for Serotonin Syndrome is also present, when combined with Tramadol. Sumatriptan is metabolized by CYP3A4 but does not directly inhibit its function, although there is a potential for competition between the two molecules, leading to a buildup of Tramadol and M1.
Tramadol and Butalbital
Butalbital is a barbiturate used in the treatment of pain and headaches (particularly tension headaches, due to their muscular component). Butalbital is a central nervous system depressant and as such, it can act additively with tramadol, increasing the risk of somnolence, lack of coordination and impaired judgement. Butalbital is a weak inducer of CYP2D6 and CYP3A4 and so can lead to an accelerated clearance of Tramadol, thus reducing its duration of action.
Tramadol and Acetaminophen, Butalbital and Caffeine (Fioricet)
Fioricet is a combination of drugs also used in the treatment of tension headaches, taking advantage of the synergistic effect of its component drugs. In this case, the risk is dominated by the Tramadol/Butalbital interaction.
Tramadol and Aspirin, Butalbital and Caffeine (Fiorinal)
Fiorinal is a combination of drugs also used in the treatment of tension headaches, taking advantage of the synergistic effect of its component drugs. In this case, the risk is dominated by the Tramadol/Butalbital interaction.
Tramadol and Sulfamethoxazole/Trimethoprim
Sulfamethoxazole in association with Trimethoprim (Bactrim) is used to treat bacterial infections, by inhibiting folate synthesis in susceptible organisms. There are no studies referencing specific interactions between this drug association and Tramadol, however they are possible. Sulfamethoxazole is an inhibitor of CYP3A4, thus there can be increased effectiveness of Tramadol, as its metabolism to the more active metabolite M1 is increased (via CYP2D6) either by direct or competitive inhibition of the metabolic pathway leading to the formation of M2.
This drug combination is also known to cause nausea and drowsiness, which can add to what is already caused by Tramadol and so patients are advised to be cautious in situations where alertness is paramount (such as driving).
Tramadol and Clarithromycin
Clarithromycin (Biaxin) is a macrolide antibiotic, used in the treatment of bacterial infections, by inhibiting protein synthesis. There was only one report of hallucinations in a patient taking Clarithromycin and Tramadol, but this does not appear to be a widespread interaction and may be the result of other factors. Clarithromycin is an inhibitor of CYP3A4 and so it can increase the effect of Tramadol, by decreasing the amount of metabolite M2 that is produced and the rate at which the conversion occurs, leaving more Tramadol to be converted to the more active metabolite M1 via CYP2D6. There may be increased risk of nausea as both Clarithromycin and Tramadol can produce this effect.
Tramadol and Cephalexin
Cephalexin (Keflex) is a beta-lactam antibiotic, used in the treatment of bacterial infections by disrupting their cell wall. There are no known interactions between Tramadol and Cephalexin, although the same liver enzyme system metabolizes them, thus having a potential for competitive inhibition and thus a lower effect for Tramadol. There may be increased risk of nausea as both Cephalexin and Tramadol can produce this effect.
Tramadol and Cefdinir
Cefdinir (Omnicef) is a beta-lactam antibiotic, used in the treatment of bacterial infections by disrupting their cell wall. Cefdinir is primarily excreted without suffering any metabolism and as such has a negligible potential for pharmacodynamic interaction with Tramadol. As with other beta-lactams it can cause nausea and so the risk for this side effect can increase.
Tramadol and Metronidazole
Metronidazole (Flagyl) is a nitroimidazole antibiotic, inhibiting the synthesis of nucleic acids in sensitive bacteria and protozoa. Metronidazole is an inhibitor of CYP3A4 and so it can increase the effect of Tramadol, by decreasing the amount of metabolite M2 that is produced and the rate at which the conversion occurs, leaving more Tramadol to be converted to the more active metabolite M1 via CYP2D6. There have also been inconclusive reports of an association between Metronidazole and Serotonin Syndrome and so there may be an added risk for this adverse reaction when taken together with Tramadol. Once again, there is added risk of nausea as both drugs can cause this side effect.
Tramadol and Ciprofloxacin
Ciprofloxacin (Cipro) is a fluoroquinolone antibiotic, inhibiting the action of the DNA gyrase enzyme in sensitive bacteria. Ciprofloxacin is a potent inhibitor of both CYP3A4 and CYP2D6, both of which are responsible for metabolizing Tramadol, thus limiting its effectiveness (with less M1 metabolite being produced) and increasing the possibility of side effects (as Tramadol itself accumulates). Ciprofloxacin also lowers the seizure threshold, a side effect that can add to that of Tramadol. Once again, there is added risk of nausea as both drugs can cause this side effect.
Tramadol and Ledipasvir/Sofosbuvir
Ledipasvir associated with Sofosbuvir (Harvoni) is an antiviral combination used to treat Hepatitis C. Neither of these drugs have metabolism via the same enzymes responsible for the that of Tramadol and thus there is little risk of pharmacodynamic interaction. As with other medication, there may be an increased risk of nausea as both these drugs and Tramadol can cause this side effect.
Tramadol and Valproate
Valproate (Depakote) and its salts like divalproex sodium are anticonvulsants, thought to act via GABAergic action, along with some other unknown mechanism. Valproate is an inhibitor of CYP3A4 and so it can increase the analgesic effect of Tramadol, by decreasing the amount of metabolite M2 that is produced and the rate at which the conversion occurs, leaving more Tramadol to be converted to the more active metabolite M1 via CYP2D6. On the other hand the central nervous system depression caused by both substances is additive, possibly leading to greater somnolence, lack of coordination and impaired judgement. Since Valproate frequently causes nausea, it is highly likely that this side effect will manifest, as Tramadol can also cause it.
Tramadol as Carbamazepine
Carbamazepine (TEGretol) is an anticonvulsant which acts via a GABAergic effect. Carbamazepine is an inducer of the CYP3A4 enzyme, thus promoting the conversion of Tramadol to its less active metabolite M2, in detriment of the more active M1, leading to lowered effectiveness. Carbamazepine has been linked with suicidal ideation and Tramadol is also suspected of causing this adverse reaction (although this is still not well established) so there may be added risk for suicide. Both drugs cause central nervous system depression and so there is an elevated risk of somnolence, lack of coordination and impaired judgement. As Carbamazepine frequently causes nausea, it is highly likely that this side effect will manifest, as Tramadol can also cause it.
Tramadol and Gabapentin
Gabapentin (Neurontin) is an anticonvulsant which acts via a GABAergic effect. Unlike other anticonvulsants, Gabapentin suffer negligible metabolism in humans and as such has a very low potential for pharmacodynamic interactions. Both drugs cause central nervous system depression and so there is an elevated risk of somnolence, lack of coordination and impaired judgement. Gabapentin has been linked with suicidal ideation and Tramadol is also suspected of causing this adverse reaction (although this is still not well established) so there may be added risk for suicide.
Tramadol and Levetiracetam
Levetiracetam (Keppra) is an anticonvulsant which acts via an unknown mechanism, that reduced nervous impulse conduction. Both drugs cause central nervous system depression and so there is an elevated risk of somnolence, lack of coordination and impaired judgement. Levetiracetam has been linked with suicidal ideation and Tramadol is also suspected of causing this adverse reaction (although this is still not well established) so there may be added risk for suicide.
Tramadol and Clonazepam
Clonazepam (Klonopin) is a benzodiazepine use as an anticonvulsant and in the treatment of panic disorders and movement. Although it is also metabolized by CYP3A4 it has no effect upon the enzyme’s activity or abundance, having no impact on Tramadol metabolism.
Both drugs cause central nervous system depression and so there is an elevated risk of somnolence, lack of coordination and impaired judgement.
Tramadol and St. John’s Wort
St. John’s Wort is a plant that can be found in Europe, North and South America and Australia, where at least 9 pharmacologically active compounds can be found. Due to the complex nature of herbal medication, not all of its effects are well described, but at least three of them seem to be linked to antidepressant activity (Hypericin) and mood regulation (Hyperforin and Adhyperforin).
St. John’s Wort preparations are used for the treatment of depression, anxiety, loss of appetite and low stamina, although the scientific evidence for effectiveness is mostly found in the case of depression.
Although herbal preparations tend to be regarded as harmless, their complex nature leads to often unpredictable interactions and, in the case of St. John’s Wort, one of the known interactions is with Tramadol, and it is considered a major interaction.
By inducing the CYP3A4 enzyme in the liver (acting upon the liver’s natural regulatory mechanisms in such a way that a greater amount of the enzymes of this group are produced), the rate at which Tramadol is metabolized into its less active M2 metabolite is greatly increased, leading to a less potent effect.
In the brain, both M1 and St. John’s Wort’s active compounds reduce serotonin reuptake, leading to a dangerously high accumulation of the neurotransmitter in the synapses, potentially to the point where Serotonin Syndrome may develop, which is characterized by:
- Blood pressure disturbances
- Tachycardia (rapid heartbeat)
- Blurred vision
As such the use of St. John’s Wort is not recommended to patients being treated with Tramadol.
The fact that many herbal preparations containing St. John’s Wort don’t explicitly mention this in their brand name (although it can be found in their composition sheet), makes it very important for patients to always let their doctors know if they are planning on starting or are already using herbal therapy.
Tramadol and Garcinia Cambogia
Garcinia Cambogia originates from India and Southeast Asia. Its medicinal use is linked to its content in Hydroxycitric Acid (like the citric acid in citrus fruits), but it is widely used as flavoring, seasoning and as a preservative.
Hydroxycitric acid has several pharmacological activities but its most notable one is as a weight loss coadjutant, while also being used as an anti-ulcerant, anti-oxidant and anti-inflammatory.
As with other herbal remedies, the association of preparations containing Garcinia Cambogia and Tramadol is not without risk. Hydroxycitric acid promotes weight loss by increasing the levels of Serotonin in the Central Nervous System (which is directly linked to loss of appetite) and reducing the synthesis of glycogen and fatty acids in the liver. The action upon the Central Nervous System is the main concern, and the increased release of Serotonin accompanied by a decrease in its uptake may lead to Serotonin Syndrome.
Once again it is important for doctors to always be aware of herbal medication patients may be or are planning to take, and for patients to remember that herbal medication is not without risk and can have severe impact together with other medication.