Inadequately treated chronic pain remains a major cause of suffering. A recent survey found that moderate to severe chronic pain affects 19% of adult Europeans (Breivik et al., 2006). Other large scale surveys in Australia (Blyth et al., 2001), Denmark (Sjogren et al., 2009) and Norway (Rustoen et al., 2004) have given similar results. These also represent a substantial socioeconomic burden (Dunn and Croft, 2004). Moreover, these surveys may underestimate the true incidence, because many patients paradoxically report their analgesia to be satisfactory despite being in pain. One study found that over 75% of patients declared themselves satisfied or very satisfied with their overall pain management, despite almost 50% reporting recent moderate to severe pain (Dawson et al., 2002). The cornerstone of treatment for moderate to severe pain is classical opioid therapy; the WHO Pain Analgesic Ladder recommends weak opioids for Step 2 and strong opioids for Step 3 in the management of chronic pain (WHO, 1996), even if this recommendation has been criticized (Marinangeli et al., 2004). However, the prescription of opioids is still limited by medical, ethical, cultural and legal issues (Bhamb et al., 2006; Jacobsen et al., 2007). One major factor is opiophobia; physicians’ and patients’ concerns about the appropriate use of opioids, and their fears and misunderstandings in connection with these agents. Patients may be reluctant to take opioids because of a perceived association with drug abuse and criminality (Fields, 2007) or with terminal illness. Classic opioid therapy also has shortcomings; specifically, in providing sustained analgesic efficacy over long periods, reliable efficacy in difficult-to-treat pain syndromes, and acceptable levels of tolerability. Balancing adequate pain relief with minimal side effects is difficult, and sometimes impossible. Long term opioid efficacy may be compromised by the development of tolerance and/or hyperalgesia. The current clinical strategy for managing these phenomena is opioid rotation, utilising the incomplete cross-tolerance between opioids in order to recover efficacy (DuPen et al., 2007). However, the evidence for this strategy is largely anecdotal or based on observational and uncontrolled studies, and there are no predictive criteria for the best drug option. A recent approach has been to combine drugs with different modes of action, such as morphine with N-methyl-D-aspartate (NMDA) antagonists, anticonvulsants or antidepressants. A few clinical studies have been undertaken with morphine plus the NMDA antagonist dextromethorphan. The combination has so far failed to demonstrate either enhanced opioid analgesia or reduced tolerance compared to morphine alone, and – in addition – discontinuation rates have been higher with the combination (Galer et al., 2005). Difficult-to-treat pain syndromes are essentially those where the pain is neuropathic in origin or has a neuropathic component. Examples include diabetic peripheral neuropathy, post-herpetic neuralgia and mixed cancer pain. Many different drugs are currently used to treat these syndromes and there is no gold standard for treatment, demonstrated by a review of 105 high-quality, randomised, placebo-controlled clinical trials (Finnerup et al., 2005). Experienced pain therapists use a combination of analgesics (often an opioid and a non-opioid) with different modes of action. Animal studies have suggested that combining morphine with an alpha2 delta ligand such as gabapentin (Matthews and Dickenson, 2002), a tricyclic antidepressant such as amitriptyline (Luccarini et al., 2004), or an NMDA antagonist such as ketamine (Pelissier et al., 2003) all offer some benefit. However, some unresolved issues remain with this approach (such as the safety of polypharmacy and its effect on compliance), while clinical trials suggest that any improvement in efficacy may be outweighed by the increased incidence of side effects (Hanna et al., 2008; Gilron et al., 2005). Tolerability problems are common with opioids, particularly nausea and vomiting during the first one or two weeks, and constipation throughout long term treatment. Anti-emetics and laxatives may be used both for prophylaxis and treatment of these adverse events, but the current pharmacological approach is often unsatisfactory and/or the regimen is too complex, so patients discontinue treatment because of additional and intolerable side effects. One recent alternative is to combine a classical opioid with a systemic mu opioid receptor antagonist (Muller-Lissner et al., 2007), but further studies are needed. Peripheral selective and non-selective mu opioid receptor antagonists have been developed. These act on peripheral receptors, including those located within the GI tract, and do not cross the blood–brain barrier. Some clinical trials has shown that subcutaneous methylnaltrexone rapidly induces laxation in patients with advanced illness and opioid-induced consti-
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Jul 1, 2010
Martin Grosshans + 6
Open Access