Induction of pain facilitation by sustained opioid exposure: relationship to opioid antinociceptive tolerance

Abstract

Opioid analgesics are frequently used for the long-term management of chronic pain states, including cancer pain. The prolonged use of opioids is associated with a requirement for increasing doses to manage pain at a consistent level, reflecting the phenomenon of analgesic tolerance. It is now becoming clearer that patients receiving long-term opioid therapy can develop unexpected abnormal pain. Such paradoxical opioid-induced pain, as well as tolerance to the antinociceptive actions of opioids, has been reliably measured in animals during the period of continuous opioid delivery. Several recent studies have demonstrated that such pain may be secondary to neuroplastic changes that result, in part, from an activation of descending pain facilitation mechanisms arising from the rostral ventromedial medulla (RVM). One mechanism which may mediate such pain facilitation is through the increased activity of CCK in the RVM. Secondary consequences from descending facilitation may be produced. For example, opioid–induced upregulation of spinal dynorphin levels seem to depend on intact descending pathways from the RVM reflecting spinal neuroplasticity secondary to changes at supraspinal levels. Increased expression of spinal dynorphin reflects a trophic action of sustained opioid exposure which promotes an increased pain state. Spinal dynorphin may promote pain, in part, by enhancing the evoked release of excitatory transmitters from primary afferents. In this regard, opioids also produce trophic actions by increasing CGRP expression in the dorsal root ganglia. Increased pain elicited by opioids is a critical factor in the behavioral manifestation of opioid tolerance as manipulations which block abnormal pain also block antinociceptive tolerance. Manipulations that have blocked enhanced pain and antinociceptive tolerance include reversible and permanent ablation of descending facilitation from the RVM. Thus, opioids elicit systems-level adaptations resulting in pain due to descending facilitation, upregulation of spinal dynorphin and enhanced release of excitatory transmitters from primary afferents. Adaptive changes produced by sustained opioid exposure including trophic effects to enhance pain transmitters suggest the need for careful evaluation of the consequences of long-term opioid administration to patients.

Introduction

Although there have been several recent advances in the therapeutic management of painful conditions, the primary drugs of choice for the treatment of moderate to severe pain remain the mu-opioid receptor analgesics, represented by such drugs as morphine and fentanyl. Whereas these opioids enjoy well-deserved and accepted clinical efficacy, the use of opioid analgesics for the treatment of many chronic pain states is often offset by the development of tolerance, defined as a decrease in analgesic activity of a drug after a previous exposure to the same or a similar drug Cox, 1990, Foley, 1993, Foley, 1995, Way et al., 1969. Opioid analgesic tolerance is well recognized experimentally and clinically, and can occur over a period of days to weeks Foley, 1993, Foley, 1995, Way et al., 1969. Clinically, the need for increasing doses of opioids in cases of chronic pain is well documented and usually presented as a major obstacle to providing adequate pain relief over a long period of time Cherney and Portenoy, 1999, Foley, 1993, Foley, 1995. In a review of the clinical experience of over 700 patients that received spinal morphine over an average of 124 days, it was found that analgesic tolerance to spinal opioid use developed to different degrees among patients, and appeared to be related to the type of pain and differences in pharmacokinetics among patients (Arner et al., 1988).

In animal studies, antinociceptive tolerance is best characterized by a rightward displacement of the analgesic dose-effect curve. Early studies had shown that the repeated daily systemic injections of morphine to mice or rats produced significant rightward shifts in the antinociceptive effect of morphine challenge in nociceptive assays Fernandes et al., 1977a, Fernandes et al., 1977b. Repeated systemic or intrathecal (i.th.) injections of morphine also produced a rightward shift in the dose-response curves for i.th. morphine in the hot-plate and tail-flick tests (Yaksh et al., 1977). Prolonged exposure to morphine pellets implanted subdermally likewise produced a significant shift to the right in the dose-effect curves for morphine given either i.th. or supraspinally Roerig and Fujimoto, 1988, Roerig et al., 1984. Despite much intensive research documenting the occurrence of antinociceptive tolerance, however, the mechanisms which underlie this phenomenon remain largely unknown.

Many studies have appropriately focused on changes occurring at the cellular level in order to gain an appreciation of the mechanisms that may drive opioid tolerance Bohn et al., 2000, Childers, 1991, Collin and Cesselin, 1991, Mayer et al., 1995, Sabbe and Yaksh, 1990 including possible alterations in coupling of G-proteins to receptors, or in activities of adenylate cyclase and protein kinases. While these changes are clearly important to observations made with sustained exposure of opioids in animals, changes in cellular mechanisms have not yet been directly related to opioid-induced changes at the systems level. Furthermore, mechanistic interpretation of preclinical studies of opioid antinociceptive tolerance is particularly difficult as many substances have been shown to block or reverse antinociceptive tolerance. A non-inclusive list of examples of substances reported to block or reverse opioid antinociceptive tolerance is summarized in Table 1. These substances include CGRP antagonists Menard et al., 1996a, Powell et al., 2000a, NO synthase inhibitors (Powell et al., 1999), calcium channel blockers (Aley and Levine, 1997), cyclooxygenase inhibitors (Powell et al., 1999), protein kinase C inhibitors (Mao et al., 1995c), competitive and non-competitive antagonists of the N-methyl, D-aspartate (NMDA) receptor, AMPA antagonists (Kest et al., 1997), superoxide dismutase mimics (Salvemini and Porreca, unpublished observations), dynorphin antiserum (Vanderah et al., 2000a), and CCK antagonists Dourish et al., 1988, Xu et al., 1992. Blockade of opioid tolerance by antagonists of NMDA receptors has been especially well studied Lutfy et al., 1996, Manning et al., 1996, Mao et al., 1995b, Mao et al., 1996, Trujillo and Akil, 1991. A concept that has been recently gaining considerable experimental validation is the hypothesis that prolonged use of opioids elicits paradoxical, abnormal pain. This enhanced pain state requires additional opioids to maintain a constant level of antinociception, and consequently may be interpreted as antinociceptive tolerance Gardell et al., 2002, Vanderah et al., 2000a, Vanderah et al., 2001a, Vanderah et al., 2001b. Here, we discuss the possible relationship of opioid-induced abnormal pain to antinociceptive tolerance.