Mechanisms of Opioid-Induced Tolerance and Hyperalgesia

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

Disclosures

Pain Manag Nurs. 2007;8(3):113-121. 

In This Article

Opioid-Induced Hyperalgesia

Opioid-induced hyperalgesia is a condition manifested clinically as hyperesthesia (i.e., dramatically increased sensitivity to painful stimuli) and/or allodynia (i.e., pain elicited by a normally nonpainful stimulus). It occurs in some patients (and, in laboratory studies, animals) receiving chronic opioid therapy; the abnormal pain often arises from an anatomically distinct region and is of a different quality than the original pain problem (Ossipov et al., 2005). Clinical reports dating back to the late 19th century documented that hyperalgesia was associated with opioid dependence. Later clinical observations and studies suggested that pain sensitivity differs between persons with opioid addiction and those who are not addicted (Compton 1994, Doverty et al 2001). In the 1940s, hyperalgesia also was described as part of the opioid withdrawal syndrome. In the past decade, research indicated that hyperalgesia also occurred in the context of short-term and continuous therapy in which physical dependence and withdrawal did not play a role (Angst & Clark, 2006).

Several mechanisms associated with opioid-induced hyperalgesia have been identified. Glutamate-associated activation of N-methyl-D-aspartate (NMDA) receptors causes spinal neuron sensitization; this pronociceptive mechanism has been implicated in the development of neuropathic pain and opioid-induced hyperalgesia. The ability of NMDA receptor antagonists such as MK801 to block opioid-associated hyperalgesia provides further evidence that NMDA receptors are involved in hyperalgesic states (King et al 2005, Mao 2006, Ossipov et al 2005).

Other studies have documented that hyperalgesia results from increased excitatory peptide neurotransmitters, such as cholecystokinin (CCK), which are released from neurons in the RVM and activate spinal pathways that up-regulate spinal dynorphin. Both of these substances act as pronociceptive agents (Dourish et al 1988, Gardell et al 2002, Vanderah et al 2000, Vanderah et al 2001, Xu et al 1992). These and other excitatory neurotransmitters are believed to cause "central sensitization" that result in hypersensitivity of the spinal cord to nociceptive inputs from the periphery. In other words, pain signals being transmitted into the spinal cord become amplified as a result of the action of these neurotransmitters.

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