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Bleeding and Elevated INR Secondary to Concomitant Tramadol and Warfarin Administration

Keith T. Veltri BPharm, PharmD
William A. Olsufka PharmD, BCPP

INTRODUCTION

Tramadol is a centrally active oral synthetic analgesic indicated for the management of moderate to severe pain. Tramadol and its major active metabolite (M1) bind to μ-opiate receptors in the central nervous system (CNS), causing the inhibition of ascending pain pathways; this alters the perception of and response to pain while weakly inhibiting the reuptake of  norepinephrine and serotonin, neurotransmitters that are involved in the descending inhibitory pain pathway.1,2

Numerous drug interactions have been well documented with tramadol, but only sporadic case reports provide evidence of an interaction between the analgesic and warfarin in certain individuals that leads to an elevated international normalized ratio (INR), bruising, and/or hemorrhage.3–10 If an interaction does occur, it will typically transpire within three to four days after the tramadol has been ingested by patients who are stabilized on warfarin. The normalization of INR can take up to several days after tramadol has been held. Clinicians should be cognizant of this interaction and closely monitor INR when it is necessary to prescribe a patient tramadol with warfarin, especially during the first week of treatment.11

Case Report

This case illustrates the use of tramadol in a patient who was already on a stable regimen of warfarin. MR, an 86-year-old female, presented to the emergency department (ED) secondary to rectal bleeding for one day. In addition, she presented with a supra-therapeutic INR of 5.4. Her pertinent medical history information included chronic atrial fibrillation, hypertension, diverticulosis, and asthma. The patient denied any nausea, vomiting, fever, chills, or vaginal/gum bleeding. Upon her admission, until the cause of hematochezia could be determined, MR was initiated on vitamin K; warfarin was held and INR laboratory values were monitored daily. A colonoscopy was performed, which showed non-bleeding internal hemorrhoids and diverticulosis in the sigmoid, descending colon, and proximal transverse colon. As no bleeding lesions were found during examination, the bleeding was thought to be secondary to diverticulosis versus hemorrhoids versus diffuse mucosal bleeding in the setting of supratherapeutic INR.

Table 1 Complete Blood Count
Test Reference Range Day 1 Day 2 Day 3 Day 4
Red Blood Cell Count 4.00–5.20 MIL/uL 4.79 5.06 5.09 5.11
Hemoglobin 12.2–15.3 g/dL 12.6 12.9 13.2 13.4
Hematocrit 36–45% 40.4 41.7 42.9 43.0
Mean Corpuscular Volume 80–96 fL 84.3 84.3 84.0 85.0
Mean Corpuscular Hgb 27–33 pg 26.1 26.1 26.2 26.3
Mean Corpuscular Hgb Concentration 33–36 g/dL 30.7 30.9 31.0 31.2
Platelet Count 150–400 k/uL 176 181 201 206
Key: Hgb = hemoglobin
Table 2 Coagulation Tests
Test Reference Range Day 1 Day 2 Day 3 Day 4
Prothrombin Time (PT) 9.5–12.0 seconds 55.8 28.9 14.0 12.6
Activated Partial Thromboplastin Time (aPTT) 26.1–33.8 seconds 34.0 30.0 NA NA

After a thorough medication reconciliation, only tramadol was found to interact with warfarin upon admission, and MR denied using any herbal or over-the-counter (OTC) agents as an outpatient. As a result, because of the potential interaction between tramadol and warfarin, gabapentin alone was continued for MR’s neuropathy. With the patient’s INR (Figure 1) and relevant blood values (Tables 1 and 2) trending toward a therapeutic range throughout her hospitalization, the medical team advised MR to continue gabapentin monotherapy for her chronic pain while they considered either dose titration or additional treatment modalities (if necessary). Warfarin was restarted for MR’s atrial fibrillation, and discharge planning was prepared on Day 4 of admission.

Figure 1 INR Laboratory Values

Key: INR = international normalized ratio

DISCUSSION

The exact mechanism of a tramadol–warfarin interaction has not been fully determined; however, it is important to investigate as warfarin, a vitamin K antagonist, remains a widely used oral anticoagulant. Interactions with warfarin are generally attributed to metabolic inhibition, additive anticoagulation effects, or, less commonly, protein displacement. Tramadol is only 20% bound to plasma proteins and therefore is not considered to cause clinically significant displacement of warfarin.3,5

It has been postulated that the effects of tramadol’s inhibition of serotonin reuptake might result in an increased bleeding tendency through a pharmacodynamic interaction similar to that of the selective serotonin reuptake inhibitor (SSRI) drug class. Serotonin is a relatively weak platelet activator, stored in platelets at rest; during platelet activation, it is released into circulation along with other factors and becomes a stimulus for platelet aggregation. A transporter protein is necessary to transport serotonin into the platelet, and, as SSRIs are antago-nists of this transporter, this could account for the impairment of hemostasis. Tramadol’s similar inhibition of the reuptake of serotonin into platelets could result in decreased clot forma -tion and a subsequent increase in the risk of bleeding. This is one possible mechanism that might have caused our patient’s hematochezia.3,5, 12–15

Warfarin is metabolized by cytochrome P450 isoenzymes (CYPs), with CYP2C9 being responsible for the majority of the metabolism of the S-enantiomer, which is more potent than the R-enantiomer, including CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. Tramadol also undergoes metabolism via several pathways, including CYP2D6 and CYP3A4. Some researchers propose that the competition for CYP3A4 metabolism increases levels of R-warfarin, prolongs the prothrombin (PT) time, and subsequently increases the INR.5

There is considerable variability in the pharmacokinetic and pharmacodynamic properties of tramadol depending on the patient’s genetic background. This has been partly attributed to CYP2D6 polymorphisms, as the enzyme plays a critical role in generating the M1 metabolite. The N-desmethylation to N-desmethyltramadol metabolite (M2) is catalyzed by CYP2B6 and CYP3A4 and is not pharmacologically active.16 

In 2004, a report from Sweden suggested that patients with mutations in the CYP2D6 gene or patients taking pharmacological inhibitors of this isoenzyme might also be at increased risk for this tramadol–warfarin interaction.3,5,10 Subrahmanyam et al. concluded in their study that individuals who carry mutated CYP2D6 alleles form less of the CYP2D6-mediated etabolite M1 and more of the CYP3A4-mediated metabolite M2, postulating that “it would be reasonable that changes in the disposition of tramadol associated with reduced CYP2D6 activity could potentially increase the risk of an interaction with warfarin.”17 Pharmacogenomic CYP2D6 laboratory testing for tramadol, however, is not routinely performed and is only available in certain centers for individualized medicine. But because clinical reimbursement rates vary, medical providers should consider contacting the laboratory or the patient’s insurance provider for details before ordering such tests.16

CONCLUSION

Concurrent administration of tramadol and warfarin warrants the close monitoring of INR levels, which can reach supra-therapeutic ranges within days and predispose the patient to potentially fatal bleeding events. The current package insert for tramadol includes a statement that post-marketing surveillance data have revealed rare instances of increases in INR levels in patients who are also receiving warfarin. It has been recommended that when tramadol is prescribed on a long-termbasis, the stable therapeutic warfarin dose should “initially be reduced by 25% with close monitoring of the INR. The INR should be rechecked no later than one week after the start of tramadol therapy.”3  The use of tramadol on an as-needed basis in patients taking warfarin is not recommended because of the drug’s potential to alter the INR response.3

Table 3 Naranjo’s Algorithm19
  Naranjo’s Algorithm:
Determination of Adverse Drug-Reaction Probability
YES NO DO NOT KNOW SCORE
1. Are there previous conclusive reports on this reaction? +1 0 0 +1
2. Did the adverse event occur after the suspected drug was administered? +2 –1 0 +2
3. Did the adverse reaction improve when the drug was discontinued or when a specific antagonist was administered? +2 0 0 +2
4. Did the adverse reaction reappear when the drug was re-administered? +2 –1 0 0
5. Are there alternative causes (other than the drug) that could have caused the reaction on their own? –1 +2 0 +2
6. Did the reaction reappear when a placebo was given? –1 +1 0 0
7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? +1 0 0 0
8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased? +1 0 0 0
9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1 0 0 0
10. Was the adverse event confirmed by any objective evidence? +1 0 0 +1
  TOTAL SCORE       8
Total score: ≥ 9 highly probable; 5–8 probable; 1–4 possible; ≤ 0 doubtful

Our patient’s Naranjo score, which assesses the probability of a drug causing an adverse event, was 8 (Table 3), indicating a probable adverse drug reaction. Thus, practitioners should be aware of the possibility of a tramadol–warfarin interaction, and consider other analgesics; at the least, caution should be employed when tramadol is prescribed for a patient, until the interaction has been investigated more thoroughly. Patients should be counseled to monitor and report signs of bleeding or bruising, and laboratory parameters should be monitored closely for elevations in PT and INR with tramadol and warfarin coadministration.18

In MR’s case, the exact interval between initiating tramadol therapy and the onset of its interaction with warfarin was not determined. Moreover, had the possibility of this interaction been recognized upon presentation, a colonoscopy might not have been warranted. Our patient was eventually counseled on alternative treatment modalities to alleviate her neuropathic pain. However, if a medical provider deems it necessary to continue a patient on current pain management with tramadol, reductions in weekly warfarin doses should be considered to prevent INR from reaching supratherapeutic levels.

Disclosure:

The authors report no financial or commercial interest in regard to this article.

Author bio: 

Dr. Veltri is Associate Professor in the Pharmacy Practice Department at Touro College of Pharmacy in New York, New York. Dr. Olsufka is a Clinical Pharmacist at Cumberland Diagnostic and Treatment Center in Brooklyn, New York.

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