Mechanisms of Opioid-Induced Tolerance and Hyperalgesia

Anna DuPen, MN, ARNP; * Danny Shen, PhD; ‡ Mary Ersek, PhD, RN†


Pain Manag Nurs. 2007;8(3):113-121. 

In This Article

Opioid Tolerance

Opioid-induced tolerance is described in the simplest pharmacologic terms as a shift to the right in the dose-response curve; in other words, a higher dose is required over time to maintain the same level of analgesia. At times, progressive disease is the reason for higher opioid requirements (Collin et al 1993, Foley 1993). Other causes of increased opioid needs are pharmacokinetic or pharmacodynamic changes. Pharmacokinetic changes occur, for example, if the drug up-regulates the activity of a metabolic process that represents a major pathway for its elimination from the body. Enzyme induction results in a gradual reduction in plasma drug concentration while the daily opioid dose remains unchanged. Pharmacodynamic tolerance occurs when a decline in drug effect cannot be attributed to pharmacokinetic factors but instead reflects drug-activated changes in the response of the neural systems. For our purposes, "opioid tolerance" refers to pharmacodynamic tolerance.

Two major theories of opioid tolerance involve changes in opioid receptors. One theory purports that receptors undergo changes that result in decreased receptor activation, or desensitization, with prolonged exposure to opioids. The other line of evidence suggests that opioid receptor down-regulation is at least partially responsible for the development of tolerance.

The desensitization mechanism involves changes in the physiology of the opioid receptors. These receptors belong to the family of G protein–coupled receptors (GPCRs). When the opioid is bound to the receptor, the associated G protein becomes "activated." Activation of G proteins eventually leads to decreasing excitability along the cell membranes of neurons in the pain pathways. This action occurs through a reduction in cyclic adenosine monophosphate (cAMP), leading to a suppression of Na+ and Ca+ channels and resulting in analgesia (Figure 2). Over time, alterations in the G protein–mediated mechanism can lead to decreased analgesia through opioid receptor desensitization (Ferguson et al 1998, Luttrell & Lefkowitz 2002, Perry & Lefkowitz 2002, Raehal & Bohn 2005, Shen & Crain 1990, Terman et al 2004, Wang et al 2005, Yoburn et al 2003). In animal models, this desensitization occurs when intracellular regulatory proteins or enzymes, such as GPCR kinases, -arrestins, and adenylyl cyclase, are activated by opioids in such a way that they "decouple" the opioid receptor from the G protein or produce a "switch" in coupling of the receptor to a "nonanalgesic" G protein, subsequently decreasing analgesic activity. Receptor desensitization has been previously associated with morphine tolerance in rats (Noble & Cox 1996, Sim et al 1996), but more recent reviews underscore how much is left to be learned about these complex intracellular mechanisms (Raehal & Bohn, 2005).

Schematic of opioid receptor mechanism.

A second mechanism believed to be responsible for opioid tolerance occurs via internalization of the opioid receptor from the cell membrane. The density of opioid receptors located on the cell membrane is governed by endocytosis, whereby the cell membrane closes around the receptor, effectively creating a bubble of cell membrane around the receptor and drawing it into the body of the cell. Once inside the intracellular environment the receptor can no longer function and is effectively down-regulated. Rats lacking one of these down-regulators (-arrestin2) continue to have prolonged morphine-induced analgesia, whereas their counterparts that do have this down-regulator develop "tolerance" to the analgesic effects (Bohn et al 2002, Bohn et al 1999). Despite this evidence, some researchers have suggested that increased internalization may actually decrease tolerance by getting desensitized receptors off the membrane and causing resensitization through new or recycled receptors being substituted (Finn & Whistler, 2001).

Various opioid agonists (e.g., morphine, methadone, fentanyl) have been shown to differ in their ability to desensitize or down-regulate opioid receptors (Arden et al 1995, Sim-Selley et al 2000, Yabaluri & Medzihradsky 1997). Some of these differences have been attributed to the "intrinsic efficacy" of the opioid agonist. Each opioid has a given level of intrinsic efficacy for the various opioid receptors. Intrinsic efficacy is a conceptual parameter that relates the number of receptors occupied to the magnitude of the receptor-mediated response. To generate a given effect, it is necessary to occupy a number of receptors out of the total population, the so called "fractional receptor occupancy" (Chavkin & Goldstein 1982, Mercadante 1999). The number of receptors that need to be occupied to create an analgesic effect is believed to be inversely proportional to the intrinsic activity; in other words, the larger the number of unoccupied receptors (receptor reserve) that exist when a drug achieves analgesia, the greater the intrinsic efficacy of the drug (Chavkin & Goldstein 1984, Duttaroy & Yoburn 1995, Ivarsson & Neil 1989, Sosnowski & Yaksh 1990).

In general, continuous treatment with opioids with lower intrinsic efficacy, such as morphine, have been known to cause a larger rightward shift in dose response (i.e., tolerance) (Saeki & Yaksh, 1993). Animal studies have shown that chronic treatment with high-efficacy opioids that have a significant receptor reserve, such as fentanyl, down-regulate fewer receptors (Sosnowski & Yaksh, 1990). However, recent studies show high-efficacy opioids actually activate more receptor-desensitizing substances (G protein–coupled receptor kinases) than low-efficacy opioids (Terman et al., 2004), leaving us again with more complexity than clarity on these opioid-related intracellular mechanisms.


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