Glial Modulation in Pain States: Translation into Humans

Opioids are among the most potent analgesic agents available for acute and post-surgical analgesia. Despite a lack of efficacy in many pain syndromes, their use in the treatment of chronic pain has increased dramatically. Long-term analgesia for those patients for whom opioids are initially effective is limited by side effects. Short-term side effects include respiratory depression, constipation, nausea and vomiting, urinary retention, pruritus, and myoclonus. These side effects range from mild, as with constipation, which can lead to poor patient compliance but can be mitigated pharmacologically, to severe, as with respiratory depression, which is the leading cause of death in opioid toxicity. Long-term side effects include analgesic tolerance, hyperalgesia (enhanced pain perception), hormonal imbalance, and immune modulation (Ballantyne and Mao 2003). It is now the standard of care to prescribe testosterone replacement for male patients and monitor all patients for immune suppression throughout long-term opioid therapy. Currently there are no effective strategies to reduce tolerance and opioid-induced hyperalgesia, which are thought to be the cause of failed long-term analgesia (Ballantyne 2007). The clinical use of opioids has increased dramatically over the past 20 years with increased recognition of the under-treatment of chronic pain and better marketing by pharmaceutical companies (Cicero, Inciardi, and Munoz 2005; Joranson et al. 2000). A salient example of this trend was the increase in the off-label use of the non-opioid gabapentin (Neurontin) for chronic pain treatment, which was driven by misinformation and false claims (Landefeld and Steinman 2009). Portenoy and Foley (1986) were the first to report on the efficacy of opioid therapy for chronic, non-malignant pain. Their retrospective case study of 38 patients found that low-dose (<20 mg per day for most patients) opioids provided adequate analgesia in a majority of cases. However, opioid treatment did not improve employment or social function. Based largely upon this landmark study, the medical use of prescription opioids increased dramatically. From 1990 to 1996, the medical use of opioids including morphine, fentanyl, and oxycodone rose by an astounding 59%, 1168%, and 23%, respectively (Joranson et al. 2000). It was not until 1997, however, that national guidelines for the expanded use of opioid analgesics to treat chronic pain were published by the American Society of Anesthesiologists and the American Pain Society (Anesthesiology 1997; Pain 1997). Following the publication of these guidelines, from 1997 to 2001 the therapeutic use of morphine, fentanyl, and oxycodone increased still further by 48.8%, 151.2%, and 347.9%, respectively. The diversion, misuse, and abuse of opioids have mirrored the increase in opioid prescriptions. From 1997 to 2001 there was an increase in the abuse of morphine-containing compounds by 161.8%, fentanyl-containing compounds by 249.8%, and oxycodone-containing compounds by 267.3% (Novak, Nemeth, and Lawson 2004). Much of this increase in the abuse of opioids is thought to be due to the increased availability of prescription opioids and the popular misconception that prescription drugs are less dangerous than non-regulated, illegal “street” drugs. The diversion and misuse of opioids has become a critical issue in their therapeutic use (Ballantyne and LaForge 2007). The alarming increase in the amount of opioids being prescribed and the ever-increasing misuse and abuse of opioids has led to the generation of new guidelines for their use (Pergolizzi et al. 2008; Trescot et al. 2008). These updated guidelines highlight many recent studies that have shown that opioids prescribed for chronic pain may be effective for short-term analgesia (Portenoy and Foley 1986) but are of indeterminate or highly variable effectiveness for long-term (>6 months) treatment. Much of this variability is due to the differences in the pain populations studied, the wide dosage ranges of opioids currently being prescribed for chronic pain (from 20 to >100 mg morphine equivalents per day), and non-uniformity in the outcomes measured (Ballantyne and Shin 2008). Limited opioid efficacy, increasing diversion and misuse, and side effects are key problems in the treatment of chronic pain. These clinical realities and insights from preclinical investigation highlight the need for the development of new analgesic agents that target non-opioid based mechanisms that include other cell types and interactions beyond neuronal actions.