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10 Articles in Volume 17, Issue #10
A Guest Editorial on Counterfeit Pain Medication: The Other Epidemic
A Model to Incorporate Functional Medicine into Chronic Pain Care
Chronic Pain and Substance-Related Disorders
Getting at the Root of Opioid-Induced Constipation (OIC) with an Osteopathic Approach
Inside FDA's Guidance on Generic Abuse-Deterrent Opioids
Neural Pathway Pain — A Call for More Accurate Diagnoses
Pain Care in a Natural Disaster
Pharmacological Interventions in Sport-Related Concussion
The Internet of Medical Things
What Type of Withdrawal Symptoms from Tramadol Might a Patient Experience?

What Type of Withdrawal Symptoms from Tramadol Might a Patient Experience?

In this Ask the Expert Q&A, pharmacologists offer alternative treatment options for pain care.

Indicated for moderate to moderately severe pain, tramadol is a centrally acting analgesic that consists of two enantiomers that contribute to its analgesic activity.1 Tramadol is metabolized via CYP3A4, CYP2B6, and CYP2D6 to produce five metabolites: M1, M2, M3, M4, and M5. The medication undergoes CYP2D6 metabolism to its active metabolite (+)-O-desmethyl-tramadol (M1), which has higher affinity for the opioid receptor compared to the parent compound (see Figure 1, next page).1

While tramadol may be a viable agent for pain relief, there are several scenarios in which a provider may recommend discontinuation of the medication. These scenarios may include inadequate pain response, intolerable side effects, and drug-drug/drug-disease interactions, among others.

Pharmacologic Overview

Both the parent drug and M1 are partial agonists of the mu opioid receptor. Additionally, tramadol inhibits the reuptake of both norepinephrine and serotonin.1 Norepinephrine reuptake inhibition is thought to play a significant role in relieving neuropathic pain from the descending nerve pathway.2 Other opioids affect pain in the ascending pathway. Given its dual mechanism of action, tramadol acts upon both the ascending and descending pathway.

Although tramadol is classified as a partial mu opioid receptor agonist, its binding affinity is 6,000 times less than that of morphine which is similar to that of dextromethorphan.3 Tramadol’s analgesic effect is produced through the combined mechanism of both opioid and non-opioid mechanisms.3 In a study by Max et al, researchers compared amitriptyline to desipramine to fluoxetine to placebo in the treatment of diabetic peripheral neuropathy (DPN).4 Their findings elucidated the importance of norepinephrine reuptake blockade for the treatment of pain associated with the DPN model and ruled out any analgesic benefit from serotonin alone.  

Symptom Comparison

According to the package insert, reported symptoms of tramadol withdrawal include anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and, rarely, hallucinations.5 Other symptoms that have been reported less frequently include panic attacks, severe anxiety, and paresthesias.5 However, given that the binding affinity of tramadol is 1/6000 of that of morphine, one might expect withdrawal symptoms to be more consistent with that of serotonin withdrawal.

Serotonin withdrawal, which may be referred to as antidepressant discontinuation syndrome, generally occurs after abrupt discontinuation of an antidepressant taken for at least 6 weeks.6 Symptoms of serotonin withdrawal may include dizziness, vertigo, nausea, headaches, insomnia, anxiety, fatigue, and mood swings. Unlike opioid withdrawal, serotonin withdrawal does not include hypertension or diarrhea as a primary symptom. However, elevated blood pressure and diarrhea may still occur as secondary withdrawal symptoms as a result of potentially heightened anxiety or irritability.

The underlying mechanism for serotonin withdrawal is thought to be due to transient deficiency of synaptic serotonin.6 On the other hand, opioid withdrawal is mediated by increased noradrenergic activity, which is the likely reason that clonidine (an alpha-2-agonist) is generally effective for managing opioid withdrawal.7 Therefore, clonidine is not expected to circumvent serotonin withdrawal from abrupt cessation of tramadol.

Tapering Strategy

Clinicians need to be familiar with strategies for the prevention and treatment of serotonin withdrawal and recognize that symptoms are often difficult to differentiate from mild to moderate opioid withdrawal. Preventive strategies include educating patients about the potential of experiencing serotonin withdrawal syndrome if tramadol dosages are abruptly stopped; providers may recommend a taper prior to discontinuation.8

Treatment strategies may also include reassurance, symptomatic control, and replenishing synaptic serotonin followed by taper is necessary. For example, fluoxetine is a selective serotonin reuptake inhibitor with long half-life that essentially is self-tapering.9 In the authors’ experience, although fluoxetine is not FDA-indicated for antidepressant discontinuation syndrome, 10 to 20 mg may be administered daily for 1 to 2 days to circumvent serotonin withdrawal symptoms.  

This article is the sole work of the authors; stated opinions or assertions do not reflect the opinions of employers or employee affiliates listed. The article was not prepared as part of the authors’ duties as federal employees.

Last updated on: December 7, 2017
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