Morphine

Morphine is approximately ten times stronger than codeine (25). While highly effective for pain relief, this strength comes with increased risks of respiratory depression, dependence, and addiction (26).

What Makes Morphine Unique?

Active Metabolites:
Morphine’s effects are not only due to morphine itself but also to its metabolites:

• Morphine-6-glucuronide (M6G): Around 50 times more potent than morphine but limited by its poor ability to cross the blood-brain barrier. It contributes about 10% to morphine’s total pain-relieving effect (30–32).
• Morphine-3-glucuronide (M3G): Has no painkilling effects and may even worsen pain and cause neurotoxic effects like confusion or lowered seizure threshold due to immune system activation (27–29).

Immune System Activation:
Chronic opioid use, including morphine, is associated with neuroinflammation and immune sensitisation. This can reduce the effectiveness of opioids over time and contribute to the development of Opioid Use Disorder (OUD) (2–5, 8).

Risk Factors for Addiction:
People with a history of:

• Childhood stress or trauma
• Brain injury
• Psychological vulnerability
  may be more prone to opioid dependence due to the way opioids interact with the immune and nervous systems (6, 7).

Pain Management Advice for Patients

• If morphine has been prescribed to you, especially for longer-term use, consider the following:

• Be open with your doctor: Discuss your full medical and psychological history, especially any past trauma or mental health issues.

• Stick to the prescribed dose: Do not increase your dose without medical advice.

• Shorter is better: Try to use morphine for the shortest time possible to achieve relief.

• Watch for changes: Report any worsening pain, low mood, or physical symptoms like sweating, yawning, or digestive issues—especially if they occur when a dose is missed.

• Don’t go it alone: If pain is not well controlled, speak to your GP or specialist rather than self-adjusting.

Morphine Side Effects

Despite its effectiveness, morphine carries a heightened risk of side effects due to its strength—around ten times more potent than codeine (25). Like all opioids, morphine can become dangerous when taken in excess or combined with alcohol or sedating medications.

Respiratory Depression: A Serious Risk

Morphine depresses the frontal cortex, reducing alertness in a way similar to sleeping tablets. It also suppresses the brainstem’s breathing centre, compromising your natural breathing reflexes (11, 12). This becomes especially dangerous when morphine is mixed with:

• Alcohol

• Benzodiazepines (e.g. diazepam, lorazepam)

• Sleeping aids or sedatives

Signs of life-threatening breathing depression include:

• Drowsiness and slowed thinking or speech

• Shallow or infrequent breathing

If these symptoms appear, seek emergency medical care immediately. Importantly, morphine also passes into breast milk—posing a severe risk to infants, particularly if the mother metabolises morphine quickly (9).

Addiction and Withdrawal

Opioid Use Disorder (OUD) can develop in both short- and long-term users. Several factors increase the risk, including:

• Psychological trauma or stress

• Traumatic brain injury

• Long-term opioid treatment (>3 months)

• Lack of social or medical support

• Use of extended-release opioids or multi-drug regimens (2, 3, 6, 8, 9, 13)

Withdrawal symptoms may include (15, 16):

• Muscle pain, tremors, sweating, diarrhoea, nausea, anxiety, insomnia, emotional blunting, yawning, goosebumps, and pupil dilation.

Just as important are the behavioural signs that someone may be developing OUD:

• Social withdrawal and loss of interest in usual activities

• Low mood or emotional instability

• Increasing doses without medical advice

• Problems at work or school

• Strained relationships with family or friends

Other Common Side Effects of Morphine

Most patients experience at least one side effect. Many subside after a few days, but itching and constipation often persist (17).

Reported frequencies from clinical studies and palliative care data include (17, 19):

• Constipation: 40–80%

• Nausea and vomiting: 25–30%

• Sedation or sleepiness: 20–60%

• Memory issues: 73–81%

• Sleep disturbances: 35–57%

• Fatigue: 9.5%

• Pruritus (itch): 2–10%

• Delirium or confusion: 21%

• Myoclonus (muscle twitching): 3–87%

• Hypogonadism in males: 63–69%

Cognitive and emotional effects are most noticeable at the beginning of treatment or after a dose increase. In older patients, opioid-induced delirium may signal an increased risk of dementia, likely due to inflammation in the brain (20, 21).

The Bottom Line

Morphine can be a valuable tool in managing serious pain, but it must be used with care. Close collaboration with your GP or pain specialist ensures the benefits outweigh the risks—particularly if you’re managing chronic pain, taking other sedating medications, or have a history of psychological stress or trauma.

Unlike many other opioids, morphine is not metabolised by CYP450 enzymes and therefore lacks official pharmacogenetic prescribing guidelines. However, differences in glucuronidation and renal function can still affect how patients respond to treatment.

While CYP genotyping isn’t relevant for morphine, clinical variability still arises—often due to age, kidney performance, or interactions that influence its active metabolites (M3G and M6G).

Although certain genetic factors may shape opioid sensitivity or immune response, these are not currently part of routine PGx testing and are not included here.

Related Medications:

Pharmacogenetic factors may be important for other opioids that rely on CYP metabolism, particularly:

• Alfentanil

• Fentanyl

• Hydrocodone

• Codeine

• Tramadol