Tramadol Addiction – The Health Risks of Chronic Use and Abuse

This is the third installment in a series of articles on tramadol. Also read part 1 - Tramadol Withdrawal and Tapering Guidelines and Part 2 – Tips on Coping with Tramadol Withdrawal Symptoms.

How harmful is tramadol abuse – what’s it really doing in your body and are you going to suffer long-term physical health consequences from your habit?

If you’re a chronic user, you’ve probably wondered about the dangers, so read on to learn more about what tramadol does in your brain and body and about the health risks associated with acute and chronic use, specifically:

• How tramadol works in the brain.
• Tramadol’s addiction potential and how it compares to drugs like oxycodone.
• Seizure risks and what exacerbates these risks.
• Overdose signs and treatments.
• Serotonin syndrome signs and treatments.
• Tramadol and neonatal abstinence syndrome.
• Tramadol’s effects on sleep, its negligible cancer profile and the potential for organ damage.
  

How Does Tramadol Work in the Brain?

Though reading the complex neuroscience behind tramadol can be tough slogging, it’s a good idea to gain at least a basic idea of what it’s doing in your brain. Here's a very brief overview of the medication's 2 primary modes of action.

Disconcertingly, scientists don’t have a total understanding of how tramadol works. Consider this quote from the medication insert, “Tramadol hydrochloride is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood.” !!! ¹

But here’s what is known:

Tramadol influences 2 primary brain systems:

1. The opioid system - by binding with u-opioid receptors.
2. the monoamine system - by inhibiting the reuptake of serotonin and norepinephrine.

Tramadol is partially metabolized in the liver by the enzymes CYP2D6 and CYP3A4. The tramadol metabolized by CYP2D6 becomes a substance called O-Desmethyltramadol. Both the original tramadol compound and O-Desmethyltramadol stimulate u-opioid receptors in the brain, though the O-Desmethyltramadol has 6 times the affinity for these receptors than the original compound.

For analgesia (and intoxication) both the opioid and serotonin/norepinephrine systems are important. We know this becasue blocking opioid receptor activation with naloxone does not completely eliminate analgesia or abuse potential.

The Acute and Chronic Risks of Tramadol Abuse

Though tramadol isn't as risky or harmful as full-agonist opiates, with short or long-term abuse you are at risk of some serious health consequences.

Addiction

If you take tramadol chronically you will develop a physical dependence and will experience withdrawal symptoms should you stop taking the drug too suddenly.

You are also at risk of addiction, which is distinct from physical dependence - especially if you ever take more tramadol than prescribed for pain management or if you ever take tramadol just to feel good.

Symptoms of Tramadol Addiction Include:

• A loss of control over your tramadol use (for example, being unable to manage your supply of medication to last between prescriptions).
• Compulsive use.
• Using tramadol for non-medical reasons (to get high).
• Continuing to use tramadol despite being aware that it does you harm or risks you harm (examples could include excessive financial harms, risks of overdose, a failure to meet responsibilities, legal problems, etc.)
• Craving tramadol.²

Tramadol was originally touted as a drug with significantly less abuse and addiction potential than comparable full-agonist opioids. While it’s still considered less addictive than full-opioids, the FDA now acknowledges tramadol’s abuse risk and advises against prescribing this drug to people considered addiction prone or those who use alcohol to excess.

If you think you’re addicted, Self-Test Your Addiction Severity and learn about why you might benefit from addiction treatment.

Study: Comparing Tramadol’s Abuse Risk to Oxycodone’s

In a study of abuse potential, researchers at the University of Kentucky College of Medicine compared tramadol, codeine, oxycodone and a placebo to see how much drug abusers liked each substance (they didn’t know what they were taking) and to see how hard they would work for further doses.

For the study:

• All subjects were non opiate-dependent recreational opiate abusers.
• To test the 3 different drugs, all subjects came in for 7 times for 2-day experimental procedures. On each day 1, researchers gave each subject one of the 4 substances; the subjects then rated this drug for recreational likeability and learned they’d be working the next day to earn doses of this substance.
• On each day 2, subjects came back in and worked (through button clicking exercises) to earn small doses of the same drug.

The Results:

• Subjects did not like the placebo and would not work for it.
• On a scale to 100, when rating how much they liked the pleasurable high, subjects gave 40 mg of oxycodone a score of a little more than 62, 200 mg of codeine a score of 49 and 400 mg of tramadol a score of 47.
• Though subjects reported liking the oxycodone high more than the tramadol high, subjects were willing to work harder to get more tramadol than they were to get more oxycodone or codeine.³
  

The Significant Risks of Seizure

High dose tramadol abuse is associated with a significant risk of seizure. Consider the following studies which illustrate the dangers.

The Belgrade Study

Researchers at Belgrade University Medical School followed a group of 57 tramadol abusers/addicts over a three year period.

• Over that three year period, 31 subjects (54%) had at least one serious seizure – 17 of them had multiple seizures over that period and 14 had a single seizure.
• Doses prompting seizures ranged from 250 mg to 2500 mg and the vast majority of seizures occurred within 24 hours of acute intoxication.
• Factors that increased the risk of seizure included: a longer history of tramadol abuse, younger age and the concurrent use of alcohol.⁴

The Baghdad Study

Out of 41 patients referred to the addiction unit of the Ibn-Rushed Mental Teaching Hospital, 20% had experienced at least one tramadol related seizure.⁵

The Iran Study

And in a review of cases from Baharloo Hospital Poison Center in Iran, out of 401 patients admitted for tramadol overdose, 30.2% reported a history of seizures.⁶

Who Is Most at Risk of Seizure?

People who take more than the recommended daily dose of tramadol are at greater risk of seizures (though seizures can occur within the recommended dosing range). You are also at higher risk of tramadol-induced seizures if you are/have:

• Epilepsy.
• A history of seizures.
• Undergoing alcohol or drug withdrawal.
• A history of head trauma.
• CNS infection or metabolic disorders.⁷

Managing Tramadol Seizures

Tramadol seizures can be managed with diazepam (Valium).

Overdose: Symptoms and Treatments

Tramadol can be lethal in very high doses. For adults, the estimated lethal dose ranges from between 3 and 5 grams.⁸ The lethal dose is lowered when taking tramadol concurrently with other CNS depressants, like alcohol or other sedatives, and overdose deaths have occurred from combinations of CNS depressants and tramadol.⁹

Most of the toxicity associated with tramadol overdose stems from excessive serotonin, and norepinephrine reuptake inhibition…too much tramadol results in too much serotonin and norepinephrine in the brain.

Tramadol overdose symptoms include:

• CNS depression - lethargy and coma.
• Seizures.
• Serotonin syndrome - tremor, muscle rigidity, agitation, hyperthermia, etc.
• Tachycardia and hypertension.
• Respiratory depression (less common).
• Nausea and vomiting.
• Anxiety and agitation.

Overdose Treatment

Since tramadol overdose is potentially lethal, it’s obviously a medical emergency that demands immediate hospital attention. Some possible tramadol overdose treatments include:

• Activated charcoal (but only after recent tramadol ingestion).¹⁰
• Benzodiazepines - for seizures.
• Naloxone for respiratory depression or coma - though this is tricky, since naloxone increases seizure risk.
• Assisted breathing.
• The symptomatic treatment of serotonin syndrome symptoms, such as cooling the body, maintaining hydration, sedating muscles and mind, etc.

Serotonin Syndrome

Tramadol is a mild serotonin reuptake inhibitor, so taking tramadol causes an upswing in neural serotonin levels.

If you take tramadol together with another drug that also increases serotonin levels, like SSRI/SNRIs, MAOIs, dextromethorphan (a cough syrup ingredient), Demerol and others - or with illicit drugs like MDMA or LSD, you risk bumping your serotonin to dangerous levels and experiencing a possibly lethal condition known as serotonin syndrome.

Symptoms of serotonin syndrome include:

• Agitation.
• Nausea and vomiting.
• Rapid heartbeat, high blood pressure and rapid changes in blood pressure.
• An elevated body temperature.
• Heavy sweating.
• Overactive reflexes.
• A loss of coordination and twitching muscles.
• Hallucinations.
• Confusion.
• Headache.
• Shivering.
• Diarrhea.¹¹

Symptoms of severe serotonin syndrome include:

• Seizures.
• Unconsciousness.
• Irregular heartbeat.
• High fever.¹²

Symptoms generally appear within minutes to hours after taking one or more serotonin raising medications.

Serotonin Syndrome Treatment

Serotonin syndrome is a possibly lethal condition that demands immediate medical attention. With appropriate treatment, symptoms will usually dissipate within 24 hours.

Typical treatments include:

• Benzodiazepines.
• Serotonin blocking drugs.
• I.V. fluids.
• Temporary induced muscle paralysis and assisted ventilation (in severe cases).

Tramadol’s Influence on Sleep

Tramadol significantly disrupts sleep quality in non-dependent or tolerant subjects.

• In a sleep study, healthy volunteers given 100 mg of tramadol experienced increased light stage 2 sleep and significantly decreased slow-wave sleep (stage 4) and REM sleep (stage 5).¹³

Chronically reduced deep and REM sleep could impair health and well-being:

• During slow wave sleep blood flows away from the brain and into muscle tissue, the body builds muscle and bone, the immune system is strengthened and the body repairs damaged tissues, such as those damaged by ultraviolet rays.
• Areas of the brain which control emotion, decision making and social functioning go dormant. Sleep scientists think this decreased activation while sleeping helps us maintain maximal social attention and functioning while awake.
  
• Deep sleep may also play a role in learning and memory encoding.¹⁴

Of course, everything depends on your individual situation. For example, if tramadol provides analgesia that increases sleep likelihood, it may have a net-positive impact on sleep quality and quantity.

Cancer and Organ Damage

There is no evidence from animal-model studies that chronic tramadol use increases human cancer risk.

Because tramadol is not associated with an increased cancer risk, or with gastrointestinal, renal or cardiovascular complications, it is considered an appropriate (safe) medication for chronic pain treatment.¹⁵

It is not, however, totally benign. Researchers who compared the long term use of tramadol to morphine in an animal-model study concluded that though tramadol was far less toxic to the liver and kidneys than morphine, it still did some damage over time.¹⁶

Use during Pregnancy/Nursing

Tramadol may slightly increase birth defect risks if used during the first 2 months of pregnancy.

If used during pregnancy, especially chronically or in high doses close to the expected date of delivery, the baby may be born with neonatal abstinence syndrome (NAS).¹⁷

Tramadol is passed through breast milk to your infant. Talk to your doctor before using tramadol while nursing.¹⁸

Medication Overuse Headache

The daily use of tramadol can cause medication overuse headaches.¹⁹