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

Clinical Implications

Pain management specialists are frequently called to consult on cases involving opioid tolerance or toxicities. Strategies for clinical management must be based on the current understanding of the complex mechanisms underlying these problems. Some strategies, such as the use of opioid-sparing therapies and opioid rotation, are currently used to prevent and treat tolerance and hyperalgesia, although the evidence supporting these practices is lacking. Other strategies such as the use of concomitant low-dose opioid antagonists to suppress G protein switching, inhibition of -arrestin2 to prevent down-regulation, or the use of CCK and NMDA receptor antagonists to suppress pain facilitation pathways are still in preclinical or early clinical studies. Pain management nurses should understand the scientific basis for current and emerging therapies.

One of the most commonly used strategies to prevent opioid tolerance and hyperalgesia is the use of adjuvant drug therapies such as anticonvulsants and antidepressants, as well as nondrug therapies such as heat, cold, and exercise programs. This approach is the cornerstone of the "opioid-sparing" principle, which aims to minimize opioid doses while providing optimal pain relief. Although there is no hard evidence that receptor desensitization or down-regulation occurs with more intensity at higher doses of opioids, many pain specialists accept the premise that an opioid-sparing treatment plan is the first step in proactively minimizing side effects and opioid tolerance (Ho et al 2006, Lauretti et al 1999, White 2005), despite evidence that challenges this principle (Kloke et al., 2000).

Opioid rotation is widely used as a treatment option to take advantage of "incomplete cross-tolerance" to recapture efficacy in a patient experiencing significant opioid tolerance or unusual sensitivity to opioid side effects. Several reports have documented success with this strategy (De Stoutz et al 1995, Drake et al 2004, Indelicato & Portenoy 2002, Kloke et al 2000, Thomsen et al 1999), although the research evidence is weak, given the poor design and small samples that characterize studies evaluating this clinical maneuver (McNicol et al 2003, Quigley 2004).

Combining opioids with low-dose opioid antagonists to prevent hyperalgesia and tolerance is an active area of study that offers some promise that the cellular mechanisms of tolerance might be circumvented. Wang et al. (2005) and Terner et al. (2006) demonstrated a significant attenuation in opioid tolerance when low-dose naltrexone was added to a morphine regimen in rats. A recent randomized controlled trial (RCT) in 350 osteoarthritis patients showed a statistically significant advantage in pain relief over time for patients treated with the combination of oxycodone and naltrexone over oxycodone alone, a clinical outcome that has been suggested to result from the suppression of G protein switching (Chindalore et al 2005, Crain & Shen 2000, Wang et al 2005). With further validation, this drug combination approach could be offered as a pre-emptive strategy in managing patients at risk of developing significant opioid tolerance.

The ability of CCK antagonists to prevent the development of hyperalgesia and tolerance has been suggested (King et al., 2005), largely based on studies with the CCK antagonist proglumide in animal models (Tang et al 1984, Watkins et al 1984). In several small clinical studies (Bernstein et al 1998, McCleane 2004, McCleane 1998, McCleane 2003, Price et al 1985), proglumide appeared to enhance opioid analgesia; whether the augmentation was attributed to reversal of tolerance and/or amelioration of hyperalgesia is debatable. To date, there have been no RCTs that fully document the efficacy of proglumide as a promoter of opioid analgesia. Moreover, studies in patients with documented opioid tolerance or hyperalgesia would be needed to demonstrate the putative counteractive effects of CCK antagonists on opioid-induced tolerance and hyperalgesia. Thus additional research is needed before CCK antagonists can be recommended in clinical practice (McCleane, 2004).

Blockade of the NMDA receptor has been shown to reduce opioid-induced hyperalgesia and retard opioid tolerance development in both animal models and human case reports (Celerier et al 2000, Clark & Kalan 1995, Davis & Inturrisi 1999, Eilers et al 2001, Elliott et al 1994, Gorman et al 1997, Haley et al 1990, Mao et al 1995, Mercadante 1996). However, one recent RCT in chronic pain patients failed to demonstrate a reduction in hyperalgesia or tolerance after three months of concurrent treatment with morphine and dextromethorphan (an NMDA receptor antagonist) compared with with morphine alone (Galer et al., 2005). Methadone, a mu agonist which also is an NMDA receptor antagonist, has been examined as an agent that can potentially prevent tolerance and hyperalgesia (Morley, 1998). Several clinical reports indicate that rotation to methadone from other opioids enhances analgesia (Benitez del Rosario et al 2004, Quigley 2004, Vigano et al 1996). In contrast, enhanced pain sensitivity in opioid addicts who are receiving methadone maintenance therapy is well documented (Compton et al 2001, Doverty et al 2001, Mao 2006). Thus, the role for methadone in the setting of hyperalgesia awaits further research.

Ongoing investigations to further define the variants of genes encoding the mu opioid receptor and on the key proteins involved in receptor desensitization and down-regulation are intriguing. If there were a simple way to test for these genetic differences in patients in the future, clinicians might have a more rational approach to optimal drug selection and drug rotation in opioid therapy.

Clinical strategies to prevent or manage hyperalgesia start with early identification of the problem. Hyperalgesia should be suspected whenever repeated dose escalation fails to provide the expected analgesic effects or when there is an unexplained pain exacerbation after an upward titration of opioid. The index of suspicion is higher if the increased pain is consistent with hyperesthesia or allodynia and other obvious causes such as disease progression or acute insult are ruled out. Hyperalgesia should be treated by reducing dose or eliminating the offending opioid. Theoretically, a reduction in the opioid dose with or without adding a replacement opioid or a gradual rotation to an alternate opioid would result in a decrease in pain. As with opioid tolerance, no RCTs exist demonstrating the superiority of one opioid over another in avoiding hyperalgesia.


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