Fentanyl

When prescribed by a specialist and taken as directed, fentanyl can be a highly effective painkiller. But due to its strength and how quickly it acts, it requires extra caution.

Fentanyl is extremely lipophilic—it dissolves in fat and rapidly crosses into the brain. This allows for fast and powerful pain relief, but it also increases the risk of opioid side effects, particularly respiratory depression (33, 34).

Why Fentanyl Is Different from Other Opioids

Fentanyl is 50 to 100 times more potent than morphine, making it highly effective for pain but also significantly more addictive and dangerous in terms of overdose risk (33, 34). Like other opioids, long-term use of fentanyl can lead to opioid use disorder (OUD)—commonly referred to as addiction. The mechanisms behind addiction are now understood to involve the immune system, not just the brain’s reward pathways. This system, which usually keeps the body healthy and balanced, becomes dysregulated over time with opioid exposure (2–8).

People with a history of early life stress, psychological trauma, or brain injury may be more vulnerable to developing opioid dependency. These factors appear to “prime” the body’s immune response to opioids, increasing the risk of chronic pain and reducing the long-term effectiveness of opioid treatment (6, 7).

Pain Management Advice for Patients Taking Fentanyl

If you have a history of trauma, stress, or brain injury, consider the following:

• Stay closely connected with your GP or pain specialist and follow the exact dose they recommend.

• Avoid prolonging treatment beyond what’s medically necessary.

• If your pain is not well controlled, do not adjust your dose—speak to your healthcare provider.

• Watch out for signs of psychological or physical dependency: low mood, loss of pleasure, irritability, or withdrawal symptoms like diarrhoea, sweating, yawning, or anxiety—particularly if a dose is missed.

These are signs that your treatment may need to be reviewed.

Medication Warnings: Interactions with Fentanyl

Fentanyl is metabolised by an enzyme called CYP3A4. If you take other medicines that inhibit this enzyme, it can increase fentanyl levels in your bloodstream and raise the risk of overdose or serious side effects.

Examples of medicines that may interfere with fentanyl include:

• Clarithromycin (a macrolide antibiotic)

• Itraconazole or ketoconazole (antifungals)

This is why your doctor or pharmacist should always review your medication list before prescribing fentanyl (9).

Fentanyl Side Effects

Fentanyl’s strength makes it very effective for pain—but also more likely to cause serious side effects if not carefully managed. Like other opioids, fentanyl can cause drowsiness, constipation, nausea, dry mouth, and low mood. Some of these effects, like nausea or tiredness, improve after a few days of regular use.

Respiratory Depression

The most dangerous side effect of fentanyl is respiratory depression—a slowing or stopping of breathing. This can happen if the dose is too high, or if fentanyl is taken with other sedatives like alcohol, benzodiazepines, or certain antidepressants. Unlike other opioids, fentanyl is fat-soluble and enters the brain rapidly, meaning breathing can slow down or stop in just minutes after overdose.

Fentanyl also binds strongly to opioid receptors, which makes it more difficult to reverse with naloxone (the emergency antidote for opioid overdose). Emergency services may need multiple doses of naloxone to counteract fentanyl’s effects.

Cognitive and Emotional Changes

Fentanyl can affect memory, concentration, and emotional regulation. People may experience confusion, anxiety, irritability, or mood swings—especially at the start of treatment or during dose adjustments. In older adults, fentanyl can sometimes trigger delirium, a sudden state of mental confusion.

Hormonal and Sexual Side Effects

Like other opioids, long-term fentanyl use can suppress hormone production, especially testosterone. In men, this may lead to reduced libido, fatigue, or even muscle loss. These changes can be subtle and often go unrecognised without blood testing.

Gastrointestinal Symptoms

Constipation is extremely common with fentanyl and usually requires active management with laxatives or other medications. Nausea and vomiting may occur when starting treatment or increasing the dose but often improve after a few days.

Skin and Muscle Effects

Itching (pruritus) and excessive sweating are common. Some people also experience myoclonus—muscle twitching or spasms—especially at higher doses or with injectable forms of fentanyl.

Opioid Use Disorder (OUD)

Fentanyl is highly addictive. People with a history of trauma, brain injury, or long-term stress are at greater risk of developing Opioid Use Disorder. Signs include a growing need to increase the dose, taking fentanyl for reasons other than pain, or struggling to stop despite side effects or relationship issues.

Withdrawal Symptoms

If fentanyl is stopped suddenly, it can cause severe withdrawal symptoms. These may include:

• Aches and chills

• Restlessness or anxiety

• Sweating, yawning, or runny nose

• Abdominal cramps, nausea, or diarrhoea

• Low mood, irritability, or insomnia

To avoid these symptoms, always work with your doctor to reduce the dose gradually.

There are currently no formal pharmacogenetic prescribing guidelines for fentanyl. This is because fentanyl is primarily metabolised by the CYP3A4 enzyme, and while genetic variations in this enzyme do exist, they are not routinely tested in clinical settings. Moreover, CYP3A4 activity is often more affected by drug-drug interactions than by genetics alone.

That said, individual variability in CYP3A4 function — due to either co-medications (e.g. macrolide antibiotics, antifungals) or inherent metabolic differences — can influence how fentanyl is processed and tolerated. Inhibiting CYP3A4 can lead to elevated fentanyl levels and a higher risk of respiratory depression, especially in patients taking other sedating medications.

Unlike opioids such as codeine or tramadol, CYP2D6 activity does not influence fentanyl metabolism, so common PGx tests covering that pathway are not clinically relevant for fentanyl use.

Related Medications:

Pharmacogenetic factors may play a more prominent role in how other opioids are processed, especially those that rely on CYP2D6 metabolism. These include:

• Alfentanil

• Morphine

• Hydrocodone

• Codeine

• Tramadol

As pharmacogenomics continues to evolve, research may uncover additional genetic contributors to fentanyl sensitivity or side effect risk — particularly around opioid receptor binding or immune response genes — but these are not currently used in clinical practice.