The impact of opioid-induced hyperalgesia for postoperative pain

Clinical evidence suggests that – besides their well known analgesic activity – opioids can increase rather than decrease sensitivity to noxious stimuli. Based on the observation that opioids can activate pain inhibitory and pain facilitatory systems, this pain hypersensitivity has been attributed to a relative predominance of pronociceptive mechanisms. Acute receptor desensitization via uncoupling of the receptor from G-proteins, upregulation of the cAMP pathway, activation of the N-methyl-d-aspartate (NMDA)-receptor system, as well as descending facilitation, have been proposed as potential mechanisms underlying opioid-induced hyperalgesia. Numerous reports exist demonstrating that opioid-induced hyperalgesia is observed both in animal and human experimental models. Brief exposures to μ-receptor agonists induce long-lasting hyperalgesic effects for days in rodents, and also in humans large-doses of intraoperative μ-receptor agonists were found to increase postoperative pain and morphine consumption. Furthermore, the prolonged use of opioids in patients is often associated with a requirement for increasing doses and the development of abnormal pain. Successful strategies that may decrease or prevent opioid-induced hyperalgesia include the concomitant administration of drugs like NMDA-antagonists, α₂-agonists, or non-steroidal anti-inflammatory drugs (NSAIDs), opioid rotation or combinations of opioids with different receptor selectivity.

Introduction

Tissue damage during surgery elicits an activation of nociceptive systems. High threshold mechano-, thermo- and chemosensors, the nociceptors (lat.: nocereb = to damage), rapidly transmit information about the degree and site of damage to the central nervous system. Depending on the type and extent of damage, sensitization processes leading to increased pain sensitivity, i.e. hyperalgesia, can be observed in the peripheral and central nervous systems (Figure 1A). Peripheral sensitization can be observed particularly during inflammation and other pathological tissue changes. They can sensitize nociceptors locally by lowering their activation thresholds or de-novo sensitize primarily insensitive, so-called ‘sleeping’ nociceptors in.1, 2, 3, 4, 5, 6Central sensitization is characterized by the increased spontaneous activity, and expansion of receptive fields of dorsal horn neurons.7, 8, 9, 10 One crucial event of this process is the activation of spinal N-Methyl-d-Aspartate (NMDA-) receptors by glutamate.11, 12, 13 Central sensitization processes can, thus, not only initiate but also maintain pain conditions that long out-last the triggering event. Furthermore, sensitization processes also appear, independent of pain perception during anesthesia and are often the basis for the development of postoperative pain.

Several publications show that perioperative antinociceptive therapy with opioids can reduce postoperative pain.14, 15, 16, 17, 18, 19, 20 Furthermore, opioids are the drugs of choice in tumor pain therapy, for the treatment of strong trauma pain, and for concomitant medication in patients with long-term artificial respiration. Thus, it is remarkable that patients with similar pain conditions often require very different quantities of opioids. Factors that influence this variability include pain type (nociceptive-, inflammatory- or neuropathic pain), psychosocial condition, and genetic disposition (gender or ethnicity).21, 22 Habituation to opioids or use of concomitant medication can also cause variation in opioid requirement.

The concept of ‘habituation’ is based on a multitude of adaptive responses of the organism to exogenous opioids. In this discussion, we include these adaptive responses in the term tolerance development.²³ The (analgesic) tolerance is characterized by decreasing analgesic effect during long-term application of opioids, necessitating dose increases (Figure 1B). Tolerance development is not based on intensified pain sensation, but can be observed even without overt pain experience.²⁴ However, not only decreasing analgesic effects are observed clinically following administration of opioids, but pain may also increase above the preexisting level of hyperalgesia.25, 26, 27, *28, *29 This would imply that the decreasing analgesic effect is based not only on a reduced antinociceptive potency of opiods, but additionally on the activation of opposing, i.e. pronociceptive systems.*30, 31, *32, *33 The basic idea of such compensatory reactions to drug application has been described in the “Opponent Process Theory”.³⁴ In this theory the interplay between a drug-induced central effect and the induced counteracting endogenous response is discussed. The drug induced effects (such as opioid-induced analgesia) have a short onset and are stable upon repetition, whereas the counteracting process (such as opioid-induced hyperalgesia) has a delayed onset, but increased upon repetition (Figure 2). According to this theory the observed effect of opioids would be determined by the interaction of the two opposing anti- and pro-nociceptive processes.³³

The molecular mechanisms underlying these anti- and pronociceptive mechanisms will be discussed below. Additionally, the relevance of these mechanisms to human and animal experimental investigation will be described and approaches to therapeutic modulation of opioid-induced hyperalgesia will be introduced.