Tolerant to Tolerance

Anesthesiology, vol. 142, pp. 438–439

Abstract

“An important issue relevant to the results of the data by Obert et al. is that tolerance is a highly dynamic phenomenon and that the dynamics of tolerance development may be distinct for the different endpoints.”Image: Adobe Stock.Opioids play an important role in the management of both acute and chronic pain, as well as in treating dyspnea and mitigate perioperative stress. Due to their effectiveness, opioids remain useful despite the numerous potential adverse effects associated with their use. One important observation is the development of tolerance to opioid analgesia requiring dose escalation to maintain the desired analgesic effect.1–3 Apart from analgesia, opioid tolerance is observed across a series of opioid effects including euphoria, reward, and respiratory depression, both in patients and individuals with an opioid use disorder.1–4 Opioid tolerance is defined as a reduction in opioid potency that develops during the course of chronic opioid use in terms of the plasma concentration causing 50% effect.4 Accordingly, we discern biologic tolerance from pseudo-tolerance, a condition that arises due to progression of disease with, consequently, the need for higher opioid doses. In the current issue of Anesthesiology, Obert et al.5 studied the development of tolerance to fentanyl in Sprague–Dawley rats. Multiple doses of 100 μg/kg were administered intravenously (10 fentanyl doses, 2 per week for 5 weeks), and various endpoints were measured, including the return of the righting reflex as a surrogate measure of return to consciousness, muscle rigidity measured by electromyography, brain activity measured by electroencephalography, and arterial blood gasses as a measure of ventilation. In their well-conducted experiments, Obert et al.5 observed that clear signs of tolerance development for the measured endpoints were absent. Striking but not completely unexpected observations were the occurrence of severe hypoxia (the arterial oxygen concentration decreased to about 45 mmHg) and hypercapnia (the arterial carbon dioxide concentration increased to about 100 mmHg) shortly after each fentanyl administration, and tonic–clonic seizures that increased in severity with repeated dosing. For the return of righting reflex, an indication of tolerance was detected during the first five to six fentanyl injections, an effect that was reversed thereafter, possibly related to the increase in seizure severity. The authors do not present data on antinociception or reward phenomena. Both human and animal data indicate that particularly these two endpoints are prone to biologic tolerance development.1–3 Additionally, tolerance to the respiratory effects of opioids have been described in humans.4 We earlier showed that the plasma concentration causing 50% effect for fentanyl-induced respiratory depression increases from 0.42 ng/ml to 1.82 ng/ml, a fourfold increase, in individuals with chronic opioid use relative to opioid-naïve individuals.4 Tolerance to opioids may be due to changes in the relationship between dose and plasma concentration (i.e., pharmacokinetics) or due to the neuroadaptive changes within the brain and brainstem (i.e., pharmacodynamics).4 For example, pharmacokinetics may be altered due to metabolic enzyme induction causing increased drug clearance or due to the upregulated activity of multidrug resistance proteins that cause the efflux of the opioid from the brain compartment or the enhanced clearance via the liver.4,6 Changes in pharmacodynamics arise from plasticity among upstream and downstream components of opioid receptor signaling, contributing to the emergence of alternative signaling pathways. Such changes include receptor desensitization (related to receptor endocytosis, degradation, and downregulation) due to intracellular neuronal upregulation of protein kinase C.7 Other mechanisms involve β-arrestin-2 recruitment, G-protein decoupling, increased adenylate cyclase activity, activation of N-methyl-d-aspartate receptors, or glia cell activation.7 Polypharmacy or abuse of multiple substances may also affect tolerance development. For example, ethanol reduces the tolerance to morphine in mice.8 This is due to protein kinase C activity inhibition by ethanol. An important issue relevant to the results of the data by Obert et al. is that tolerance is a highly dynamic phenomenon and that the dynamics of tolerance development may be distinct for the different endpoints. For example, tolerance to the development of opioid-induced respiratory depression develops much slower than analgesic tolerance, possibly due to lower protein kinase C levels in the brainstem neurons that control respiration.8 The dynamics of opioid tolerance may be the cause of lethality. After even a short period of abstinence, such as after detoxification or incarceration, tolerance to respiratory depression may be lost, elevating the risk of overdose and fatality upon relapse.9 Whether this relates to other endpoints as well remains unknown, but is certainly expected. The observation of lack of tolerance to fentanyl for the endpoints muscle rigidity, brain excitation, and respiratory depression in the Sprague–Dawley rat is seemingly difficult to align with the observations of tolerance to analgesia and respiratory depression in humans. We argue that the protocol by Obert et al. may not allow definite conclusions regarding the lack or presence of tolerance to the return of the righting reflex since the severe hypoxia and hypercapnia may have caused increasing brain damage over time with increasing neuroexcitation and difficulty regaining consciousness. With respect to the other endpoints, the evident species differences as well as the dynamics of tolerance development that differ among endpoints may be the cause for the lack of an obvious tolerance effect seen in this rat strain. This may particularly be true for short-lasting fentanyl-induced respiratory depression. Possibly, more frequent fentanyl exposures (three to four times per week) at somewhat lower doses to preclude severe hypoxia development would have unearthed tolerance. Studies in mice and rats, with alternative protocols and different genetic backgrounds and measurement of opioid plasma concentrations, may be needed to elucidate the mechanisms behind the presence or absence of tolerance to repeated opioid exposures. For now, the data from Obert et al.5 demonstrate the complexity of opioid behavior with respect to opioid tolerance development on different endpoints, some of which were unexpected but may be explained by the interactive effects induced by the consequences of single high-dose opioid administrations such as hypoxia and hypercapnia as well as the possibly rapid cycling between the different neuroadaptive states induced by fentanyl. Competing Interests Dr. Niesters and Dr. Dahan received funding from the Dutch Research Council (NWO, The Hague, The Netherlands) in the framework of the NWA-ORC call for research project TAPTOE, Tackling and Preventing the Opioid Epidemic (NWA.1160.18.300) and awards/grants from the U.S. Food and Drug Administration (Silver Spring, Maryland). Dr. Dahan received consultancy fees from Zmi Pharma (Carlsbad, California), Trevena Inc. (Chesterbrook, Pennsylvania), and Enalare Therapeutics Inc. (Princeton, New Jersey) unrelated to the current article and reimbursements from Takeda Pharmaceuticals International AG (Switzerland).

Authors 2

1. Marieke Niesters Aachen Centre for Human Drug Research (CHDR)

   Leiden University Medical Center · Centre for Human Drug Research

   Affiliation as printed

   Department of Anesthesiology and Pain Medicine, Leiden University Medical Center, Leiden, The Netherlands; Centre for Human Drug Research, Leiden, The Netherlands

   Centre for Human Drug Research, Leiden, The Netherlands

2. Albert Dahan corresponding Aachen

   Leiden University Medical Center · Outcomes Research Consortium

   Affiliation as printed

   Leiden University Medical Center, Leiden, The Netherlands; MediD Consultancy Group, Amsterdam, The Netherlands; Outcomes Research Consortium, Houston, Texas

   Leiden University Medical Center, Leiden, The Netherlands

   Outcomes Research Consortium, Houston, Texas