What is opioid-induced itch?
Pruritus, commonly known as itch, is a familiar sensation that most people experience from time to time. It is described as an unpleasant feeling in the skin that makes you want to scratch. While occasional itching is usually harmless, persistent itching can be distressing and may significantly affect a person’s quality of life.
Opioid medicines are widely used for short-term relief of moderate to severe pain, including after surgery and for cancer-related pain. However, itching is a well-known side effect of these medicines. The highest rates of opioid-induced itch, between 30% and 90%, have been observed when opioids are given near the spinal cord, a method known as neuraxial administration.
A narrative review published in the European Journal of Pain explored what is currently known about the mechanisms behind opioid-induced itch, how it relates to pain pathways, and which treatment approaches have been studied. This article summarises the key findings from that review.
How are itch and pain related?
One of the most puzzling aspects of opioid-induced itch is the close relationship between itch and pain. Both sensations travel through similar nerve pathways, using the same types of nerve fibres, called C-fibres and A-fibres. Several chemical messengers, including histamine and serotonin, play roles in both itch and pain signalling.
Despite these overlaps, opioids have opposite effects on the two sensations: they reduce pain but can trigger or worsen itching. According to the review, this paradox may be explained by specific differences at the level of the spinal cord, where specialised nerve cells appear to process itch and pain signals differently.
The review describes several theories that researchers have proposed to explain this, including the idea that there may be dedicated “labelled lines” for itch signals, and alternative models involving inhibitory nerve cells that normally keep itch signals in check.
What causes opioid-induced itch?
The review describes two broad categories of mechanism:
Peripheral mechanisms (at the skin level)
When certain opioids such as morphine or codeine interact with immune cells called mast cells in the skin, these cells may release histamine and other itch-promoting substances. However, the review notes that research in primates suggests this may not be the main driver of opioid-induced itch. This could explain why antihistamines, which are commonly used for other types of itch, often have limited effect on opioid-induced itching.
Central mechanisms (at the spinal cord level)
The review indicates that central mechanisms are likely the primary cause of opioid-induced itch in humans. When opioids activate mu-opioid receptors (μ-opioid receptors) in the spinal cord, they appear to suppress inhibitory nerve cells that normally prevent itch signals from being transmitted. This process, known as spinal disinhibition, allows itch signals to amplify.
Several key chemical messengers are involved in this process, including substance P, gastrin-releasing peptide (GRP), and natriuretic polypeptide B (NPPB). The review highlights that NPPB appears to be critical for both histamine-related and non-histamine-related itch pathways.
Did You Know?
The face, neck, and upper chest are the most commonly affected areas in opioid-induced itch, particularly when opioids are administered near the spinal cord. The review notes this is likely related to the high density of opioid receptors in the trigeminal nerve region, which processes sensory input from the face.
What treatment approaches have been studied?
The review examined several categories of treatment that have been investigated in clinical and preclinical studies:
Opioid receptor antagonists
Medicines that block mu-opioid receptors, such as naloxone, have been found to reduce opioid-induced itch. However, the review notes that these medicines may also reduce the pain-relieving effects of opioids, which limits their practicality. Low-dose continuous infusions of naloxone may help balance itch relief with ongoing pain management, though the appropriate dose varies between individuals.
Mixed agonist-antagonist opioids
Medicines such as nalbuphine, pentazocine, and butorphanol combine the blocking of mu-opioid receptors with the activation of kappa-opioid receptors. According to the review, this combination may help reduce itch while maintaining pain relief. Several randomised controlled trials have examined these medicines, with the review noting that nalbuphine in particular appeared to reduce the incidence of opioid-induced itch. However, increased drowsiness was reported as a potential side effect.
Serotonin (5-HT3) receptor antagonists
There is anatomical and mechanistic evidence supporting a role for serotonin in opioid-induced itch. Some studies have found that ondansetron and similar medicines may reduce itch after spinal opioid administration. However, the review highlights that clinical results have been mixed, with several trials showing no benefit. The authors note that further large-scale trials are needed.
Gabapentinoids
Gabapentin may help reduce opioid-induced itch by restoring the balance of inhibitory nerve signalling in the spinal cord. The review describes studies suggesting it may reduce the incidence, severity, and duration of itch. However, potential side effects include dizziness, drowsiness, and visual disturbances, so careful monitoring is important.
Other approaches
The review also discusses several other treatments with less consistent evidence, including propofol, dopamine D2 receptor antagonists (such as droperidol), non-steroidal anti-inflammatory drugs (NSAIDs), and N-methyl-D-aspartate (NMDA) receptor antagonists (such as ketamine). While some individual studies have shown potential benefits, the overall evidence base for these treatments remains limited or conflicting.
Summary of Treatment Evidence
Among the approaches reviewed, mu-opioid receptor antagonists (such as naloxone) and mixed agonist-antagonist opioids (such as nalbuphine) were associated with the strongest reported reductions in opioid-induced itch, supported by moderate to strong evidence from both animal and human studies. However, pure mu-opioid antagonists may also reduce pain relief, whereas mixed agonist-antagonists may preserve it.
Serotonin (5-HT3) receptor antagonists such as ondansetron showed inconsistent results across trials, with some studies reporting benefit and others finding no effect. Gabapentinoids such as gabapentin were associated with moderate itch reduction in several studies without apparent impact on pain relief, though side effects such as drowsiness were noted.
Evidence for other approaches, including propofol, dopamine D2 receptor antagonists, NSAIDs, and NMDA receptor antagonists such as ketamine, was described as limited or conflicting. Some of these showed promise in individual studies, but findings were not consistent across trials. Ketamine evidence was largely confined to animal models.
What does this mean for patients?
The review concludes that opioid-induced itch is a complex condition involving multiple pathways. Because opioid effects vary significantly from person to person, a one-size-fits-all approach to treatment is generally not suitable.
The authors suggest that the most promising approach may involve reducing opioid doses where possible through a multimodal pain management strategy, alongside targeted anti-itch treatments. This could include using mixed opioid receptor medicines that aim to reduce itch without compromising pain relief.
If you are experiencing itch as a side effect of opioid medication, it is important to discuss this with your prescribing clinician. They can assess your individual situation and consider whether adjustments to your pain management regimen may be appropriate.
Study Limitations
- This was a narrative review, not a systematic review or meta-analysis. The selection of studies was at the authors’ discretion rather than following a predefined protocol.
- Many of the treatment studies reviewed were small in size and some findings were based on animal models, which may not directly translate to human outcomes.
- Several treatment approaches showed conflicting results across different trials, highlighting the need for further high-quality research.
- The review focused primarily on opioid-induced itch in acute/perioperative settings. Findings may not apply equally to patients on long-term opioid therapy.
Opioids, itch, and emerging research areas
As highlighted in this review, managing the balance between pain relief and side effects such as itch remains a significant challenge for patients taking opioid medicines. There is growing interest in understanding how different treatment combinations might help optimise this balance.
Some areas of early-stage research have explored whether medical cannabis may have potential roles in pain management strategies and in managing certain types of chronic itch, such as that associated with skin conditions. However, this remains an emerging area and further clinical research is needed before firm conclusions can be drawn.
Medical cannabis is a prescription-only medicine in the UK. It is typically only considered when other treatments have not provided adequate relief. Any decision about treatment should be made in consultation with a qualified healthcare professional who can assess your individual circumstances.
If you are living with chronic pain and would like to understand the full range of treatment options that may be available to you, including whether you might be suitable for a specialist consultation, you can speak to your GP or complete an eligibility assessment with Curaleaf Clinic.
