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

Abstract and Introduction

Opioid tolerance and opioid-induced hyperalgesia are conditions that negatively affect pain management. Tolerance is defined as a state of adaptation in which exposure to a drug induces changes that result in a decrease of the drug's effects over time. Opioid-induced hyperalgesia occurs when prolonged administration of opioids results in a paradoxic increase in atypical pain that appears to be unrelated to the original nociceptive stimulus. Complex intracellular neural mechanisms, including opioid receptor desensitization and down-regulation, are believed to be major mechanisms underlying opioid tolerance. Pain facilitatory mechanisms in the central nervous system are known to contribute to opioid-induced hyperalgesia. Recent research indicates that there may be overlap in the two conditions. This article reviews known and hypothesized pathophysiologic mechanisms surrounding these phenomena and the clinical implications for pain management nurses.

Opioid analgesics continue to be the mainstay of pharmacologic treatment of moderate to severe pain. Many patients, particularly those with advanced cancer, require chronic high-dose opioid therapy. Achieving clinical efficacy and tolerability of such treatment regimens is sometimes hindered by two opioid-related phenomena. The first is tolerance, which is manifested clinically by the need for increasing opioid dosages over time to maintain the same level of pain relief; this increased need is not explained by disease progression. A second problem that arises is the more recently recognized phenomenon of opioid-induced hyperalgesia (Sjogren et al., 1998). In this situation, prolonged administration of opioids results in a paradoxic increase in atypical pain that appears to be unrelated to the original nociceptive stimulus.

Opioid-induced tolerance and hyperalgesia have been documented in both animal and human studies. They can develop after administration of several types of opioids delivered via various routes, doses (i.e., ultra-low through high dosages), and administration schedules (i.e., intermittent vs. continuous) (Angst & Clark 2006, Mao 2006, Ossipov et al 2005). Cellular changes associated with these phenomena have been identified at many anatomic sites, including afferent neurons, the spinal cord, brain, and the descending modulatory pathway (Gardell et al 2006, King et al 2005, Mao et al 2002, Ossipov et al 2005, Terman et al 2004).

Significant clinical challenges arise from opioid-induced tolerance and hyperalgesia. More effective pain treatment can be achieved when these conditions are recognized and managed. Although the mechanisms underlying opioid-induced tolerance and hyperalgesia are not completely understood, research has begun to reveal some of the complex factors that are associated with these phenomena. The purpose of the present article is to describe both the established and the hypothesized mechanisms underlying opioid-induced tolerance and hyperalgesia. The clinical implications of these mechanisms and their possible prevention and treatment also are discussed.


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