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Why do opioids sometimes not work?

In this article, Dr Fausto Morell-Ducos discusses the different causes of opioid-resistant pain.
Man sitting at computer at desk, head in hand, also holding jar of pills
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You may have been in a situation in which a patient continues to experience severe pain postoperatively in spite of large doses of morphine being administered. Or perhaps you’ve heard a patient say that a particular opioid drug simply does not work for them.

In this article, Dr Krishna Vinnakota, Anaesthesia Core Trainee at the Royal Free Hospital, and Dr Fausto Morell-Ducos, Consultant in Anaesthesia and Pain Medicine at UCLH, discuss some of the reasons why sometimes pain can be resistant to opioid analgesia.

Although opioids remain a cornerstone of the management of postoperative pain, there is great inter-individual variability in the response experienced by patients to the same opioid drug, and different types of pain have been shown to respond to opioids differently.

There are therefore many possible causes for opioid-resistant pain. It is important to recognise it and to understand the possible mechanisms behind this phenomenon, as often administering more of the same opioid drug is unlikely to help.

Genetic Polymorphisms

Variabilities in pharmacokinetics (‘what the body does to the drug’) and pharmacodynamics (‘what the drug does to the body’) can lead to significant differences in response to the same opioid drug in different people.

These differences are largely due to the presence of different versions of genes, present at such rates as to be considered normal variants within a population, known as genetic polymorphisms.

These polymorphisms are present in many of the genes coding enzymes involved in the metabolism of opioids. Codeine, oxycodone, hydrocodone, and tramadol are prodrugs. They have little affinity for opioid receptors themselves, but are metabolised to active mu-agonists by the cytochrome P450 enzyme CYP2D6. The gene coding for this enzyme is one of the most variable among all CYP genes.

The genetic polymorphisms affecting CYP2D6 result in differences in how actively this enzyme metabolises opioids. Depending on the combination of alleles an individual may have, three categories have been described: ultra-rapid metabolisers, normal metabolisers or poor metabolisers [1].

Poor metabolisers will obtain little pain relief from these opioid pro-drugs, whereas ultra-rapid metabolisers may experience more analgesia but are also at increased risk of side-effects. This has led to case reports of excess sedation and even death among patients taking some of these opioids, or in the babies of nursing mothers who are ultra-rapid metabolisers after taking codeine, for example.

For other drugs, such as pethidine, which is an opioid drug metabolised by CYP2D6 to an inactive metabolite, ultra-rapid metaboliser status results in decreased efficacy.

The frequency of the different metaboliser groups varies in different populations: CYP2D6 ultra-rapid metabolisers prevalence ranges from 0.5% in China to 29% in Ethiopia [2].

Similarly, more than 100 polymorphisms have been identified in the gene for the mu-opioid (MOP) receptor, OPRM1. One particular polymorphism, termed A118G [1], has been described. It has a global average frequency of approximately 20%, with a wide variation ranging from 3% in individuals of African descent to 50% in those of Asian descent [2]. There is evidence to suggest that having one copy of this allele is associated with lower post-operative pain thresholds and higher opioid consumption.

There are likely to be many other polymorphisms which also affect the pharmacodynamic and pharmacokinetic properties of opioids, and to date there are no readily available tests to identify these clinically. The ability to do so, however, would offer tantalising opportunities in the choice of medication we use for patients postoperatively.

Neuropathic pain

Neuropathic pain (which is pain caused by a lesion or disease of the somatosensory nervous system) can occur acutely after surgery, being present in 3-10% of general surgical patients, depending on the operation and population. It is more common after certain procedures (e.g. thoracotomy or limb amputation, where it can affect up to 50-85%) [3] and often results from traumatic, inflammatory or infective processes leading to nerve injury.

It can often present as difficult-to-manage, opioid-resistant pain, and can be difficult to diagnose. Although there are many screening questionnaires which can be used for this purpose, they are not validated in the postoperative setting, and there is no diagnostic standard for acute neuropathic pain.

Opioids are less effective in neuropathic pain than they are in nociceptive pain. Some national guidelines advise against the use of opioids in neuropathic pain altogether, whilst others support only their short-term use as second- or third-line agents.

Within the neuropathic pain subtypes, opioids are more effective in peripheral neuropathic pain than in spinal central neuropathic pain and are least useful in supraspinal central neuropathic pain.

Various Cochrane reviews have found insufficient evidence to either support or advise against the use of individual opioids in treating neuropathic pain, although some guidelines recommend tramadol and tapentadol as the opioids of choice.

A recent systematic review estimates the combined number-needed-to treat (NNT) of strong opioids in neuropathic pain to be 4.3 and that of tramadol in particular to be 4.7. Maximum effectiveness seemed to be reached at 180 mg oral morphine equivalents daily, and opioid therapy appears to be most effective within the first 12 weeks [4].

Many current treatment recommendations for acute neuropathic pain are extrapolated from chronic neuropathic pain guidelines and also include the use of ketamine and gabapentinoids.

Why opioids are less effective in neuropathic pain has not been established conclusively. There is some evidence that there may be a reduction in opioid receptor expression in some neuropathic pain states, and it may also be that some of the pro-nociceptive mechanisms involved in neuropathic pain involve parts of the pain pathways which bypass the endogenous opioid system [4].

Other Causes of Opioid-Resistant Pain

Other reasons why pain may not respond adequately to opioid analgesia include the pre-existing presence or development of opioid tolerance or opioid-induced hyperalgesia. We will look at these more closely in Step 2.13. Of note, increased pain due to opioid tolerance would be expected to respond to increase opioid dosage, whereas in opioid-induced hyperalgesia this would cause worsening of pain.

Another important cause for apparent opioid resistance can be a significant increase in nociceptive input due to tissue injury caused by a postoperative complication such as infection, anastomotic breakdown, compartment syndrome or urinary retention, among others.

Other non-nociceptive pain states have been shown to respond poorly to opioid analgesia, and require specific non-opioid pharmacological management. These include nociplastic pain, which is seen as a result of central sensitisation in chronic pain states.

It can often be difficult to differentiate these special entities from nociceptive post-operative pain, as there are no diagnostic tests which can unequivocally distinguish them. It is therefore essential to carry out a thorough clinical assessment and examination in situations where unusually high analgesic requirements or abnormal pain trajectories are seen.

Your turn now

Use the comments section below to share your thoughts and experiences.
Consider whether you think the incorporation of patient genotyping could help in advancing pain treatment? What potential impacts could this advancement lead to? Have you had experience of managing neuropathic pain postoperatively? What techniques have you seen used in its management?

Please do not share any details that could be patient-identifiable. You can ‘like’ and comment on other learners’ comments, as well as ‘follow’ other learners so you don’t miss their comments.


1. Vieira CMP, Fragoso RM, Pereira D, Medeiros R. Pain polymorphisms and opioids: An evidence based review. Mol Med Rep 2019;19:1423-1434.

2. Kumar S, Kundra P, Ramsamy K, Surendiran A. Pharmacogenetics of opioids: a narrative review. Anaesthesia 2019;74:1456-1470.

3. Schug SA, Palmer GM, Scott DA, Alcock M, Halliwell R, Mott JF; APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine (2020), Acute Pain Management: Scientific Evidence (5th edition), ANZCA & FPM, Melbourne.

4. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. The Lancet Neurology. 2015;14(2):162–73.

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Opioids and Surgery

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