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-Induced Tolerance and Hyperalgesia: Two Sides of the Same Coin?

The major clinical manifestation of opioid-induced tolerance and that of hyperalgesia are the same; that is, increasing opioid doses are necessary to achieve adequate analgesia (Angst & Clark 2006, King et al 2005, Mao 2006). Moreover, there are similarities in the mechanisms that cause tolerance and hyperalgesia. For example, CCK-mediated changes in the descending modulatory pathways appear to contribute to both opioid-induced tolerance and hyperalgesia (King et al., 2005). There also is evidence that tolerance and hyperalgesia share common cellular mechanisms that are related to changes in NMDA receptors (Mao et al 1994, Mao et al 2002).

The similarities between mechanisms causing tolerance and hyperalgesia suggest that some targeted therapies can prevent or reverse both phenomena. While this strategy has been shown to be effective in preclinical and clinical studies, Mao urged caution with this approach (Mao 2002, Mao 2006). He pointed out that hyperalgesia is characterized by different clinical features than tolerance. These features include pain intensity that is higher than the severity of the original pain problem, pain that is poorly defined in terms of quality and location, and changes in pain threshold and tolerability. These distinct features indicate that at least some of the cellular mechanisms underlying tolerance and hyperalgesia differ between the two entities. Hyperalgesia represents increased sensitivity to pain, whereas tolerance may reflect decreased sensitivity to opioids. Most importantly, unlike tolerance, opioid-induced hyperalgesia would worsen after an increase in opioid dose, whereas pain related to tolerance would be relieved by an increase in opioid dose (Mao 2002, Mao 2006).


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