Opioid Tolerance
Also see opioid tolerance in the ICU – Intensive Care Unit Opioid tolerance is a common cause for the failure of opioid analgesia. Exposure to an opioid, particularly as the sole analgesic, gives rise to pharmacodynamic tolerance (loss of activity, not due to faster drug clearance but to decreased analgesic effect). Tolerance develops to the adverse effects of opioids, namely sedation, hypoventil
Also see opioid tolerance in the ICU – Intensive Care Unit
Opioid tolerance is a common cause for the failure of opioid analgesia. Exposure to an opioid, particularly as the sole analgesic, gives rise to pharmacodynamic tolerance (loss of activity, not due to faster drug clearance but to decreased analgesic effect). Tolerance develops to the adverse effects of opioids, namely sedation, hypoventilation and nausea, but not to constipation and miosis.
Tolerance results from alterations in G-protein coupling to the opioid receptor, changes in receptor trafficking between the neuronal surface and cytoplasm, and an increase in the number and sensitivity of NMDA receptors as a result of central sensitisation.
Tolerance in the perioperative setting can be attenuated by preventive and/or prolonged blocking of pain impulses along the pain pathway through the following non-opioid agents:
- Local analgesics as a continuous local, regional or neuraxial infusion.
- Paracetamol and an NSAID, used before considering opioids.
- De-escalating opioids as soon as possible.
- Multimodal analgesia (co-analgesia): apart from paracetamol and an NSAID, a combination of usually two analgesics with different pharmacodynamics (e.g. an opioid, ketamine, dexmedetomidine and a gabapentanoid).
Regarding multimodal analgesia, it is difficult to interpret studies due to the heterogeneity of the studies: number of studies included, number and type of participants, studies used different drug combination, different dose ratios. Studies also administer analgesics according to different regimens, for example, PCA of (usually) two drugs, always an opioid with a nonopioid in the same mixture, PCA an opioid with a concurrent non-opioid infusion, concurrent (in the same mixture) infusion of an opioid plus a non-opioid, concurrent (in the same mixture) infusion of two non-opioid with addition of a low-dose opioid on a prn basis, and different opioids.
Several of these combinations have been tested; anaesthesiologists, using fuzzy logic (an integration of a sound knowledge of experience), are very good at compiling these recipes. Very often, these recipes are found in meta-analyses, which often both confirm the utility of these combinations, and also point out the deficiencies of studies or the fallacies of some combinations.
Primary outcomes usually are postoperative pain intensity, opioid consumption over different periods, and patient satisfaction. Secondary outcomes usually include sedation, hallucinations, hypoventilation, hypoxaemia, hypotension, brady- or tachycardia, nausea, vomiting and pruritus.
Postoperative PCA opioid-dexmedetomidine combinations decrease pain intensity, opioid consumption and adverse effects, as compared to an opioid only.
An example of an opioid-dexmedetomidine PCA regimen is that of Nie et al.:
- Mixture: sufentanil 100 µg + dexmedetomidine 300 µg diluted to 100 ml (This is a very expensive mixture)
- Background infusion: sufentanil 0.015 µg/kg/h + dexmedetomidine 0.045 µg/kg/h
- PCA dose: sufentanil 0.023 µg/kg + dexmedetomidine 0.07 µg/kg
- Lockout interval: 8 minutes
An example of an opioid-ketamine PCA regimen is that of Javery et al.:
- Mixture: morphine 100 mg + ketamine 100 mg diluted to 100 ml
- No background infusion
- PCA dose: 1 ml
- Lockout interval: 6 minutes
Once opioid tolerance is diagnosed, the following steps may be taken:
- Management is similar to that of ANP, including amitriptyline or gabapentanoids.
- The patient may continue with the normal opioid dose, while additional doses are administered, either intravenously or via a transcutaneous patch.
- Opioid rotation may be applied in the tolerant patient. There are significant differences in the interaction between different µ agonists and the µ-receptor which go beyond the effect on second messenger systems after binding, including the rate of receptor trafficking, and possibly even effects on receptor synthesis and affinity. In view of this, a patient experiencing inadequate analgesia from one opioid drug may be switched to slow-release morphine, or oxycodone. Transdermal fentanyl should be avoided due to the likely development of hyperalgesia. A switch back to the previous drug may prove effective should analgesia on the new drug become inadequate over time. A patient on maintenance opioids for chronic pain in the perioperative setting should be managed with a different opioid for perioperative analgesia. The following approach to opioid rotation is used:
- Calculate the equianalgesic dose of the new opioid based on equianalgesic tables.
- Start the new opioid at a dose 25–50% lower than the calculated equianalgesic dose.
- Select an appropriate dose within this window, using clinical judgment as to the applicability of the equianalgesic dose table to the specific characteristics of the opioid regimen (i.e. p.o. or IVI).
- Reassess pain severity to determine whether an additional 15–30% dose increase or decrease should be allowed to improve efficacy or to minimise adverse effects.
- Evaluate the response frequently and titrate dose of the new opioid up or down to optimise the effect. If supplemental doses are used, these should constitute 5–15% of the total daily dose and should be administered according to dose intervals appropriate for the particular opioid.
South African Society of Anaesthesiologists (SASA) Guidelines for the Management of Acute Pain in Specific Scenarios 2022