Pain and Poppies: The Good, the Bad, and the Ugly of Opioid Analgesics

Abstract

Treating pain is one of the most difficult challenges in medicine and a key facet of disease management. The isolation of morphine by Friedrich Sertürner in 1804 added an essential pharmacological tool in the treatment of pain and spawned the discovery of a new class of drugs known collectively as opioid analgesics. Revered for their potent pain-relieving effects, even Morpheus the god of dreams could not have dreamt that his opium tincture would be both a gift and a burden to humankind. To date, morphine and other opioids remain essential analgesics for alleviating pain. However, their use is plagued by major side effects, such as analgesic tolerance (diminished pain-relieving effects), hyperalgesia (increased pain sensitivity), and drug dependence. This review highlights recent advances in understanding the key causes of these adverse effects and explores the effect of chronic pain on opioid reward. Opioids and pain: scope of the problemIt is estimated that 20 -30% of Americans suffer from chronic pain, which is similar to that reported in Canada, Australia, and European countries (Blyth et al., 2001; Breivik et al., 2006;Johannes et al., 2010;Schopflocher et al., 2011). Equally striking is that chronic pain is among the most common forms of chronic illness afflicting individuals younger than 60 years of age (O'Connor, 2009). Chronic pain is also a major cause of disability (Manchikanti et al., 2013), and it is the cardinal feature of a diverse spectrum of diseases, including arthritis, migraine, cancer, metabolic disorders, and neuropathies. Treating pain in these diseases is notoriously difficult and often requires opioids, the most potent class of drugs used for controlling pain. Opioids are particularly effective for treating acute moderate-to-severe pain after surgery or trauma, and they are quintessential drugs in a physician's pharmacological toolbox for managing chronic pain. In 2012, physicians in the United States wrote Ͼ259 million opioid prescriptions, which equates to one bottle of pills for every adult American (according to the Centers for Disease Control and Prevention). Consumption of prescription opioids is highest in the United States and Canada, and, in these countries, opioid use for managing pain continues to grow (Gomes et al., 2014). Long-term opioid exposure can result in the development of analgesic tolerance, the hallmark feature of which is a loss in pain- Significance StatementChronic pain is pervasive and afflicts Ͼ100 million Americans. Treating pain in these individuals is notoriously difficult and often requires opioids, one of the most powerful and effective classes of drugs used for controlling pain. However, their use is plagued by major side effects, such as a loss of pain-relieving effects (analgesic tolerance), paradoxical pain (hyperalgesia), and addiction. Despite the potential side effects, opioids remain the pharmacological cornerstone of modern pain therapy. This review highlights recent breakthroughs in understanding the key causes of these adverse effects and expl...

Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain

“…Whereas morphine and opioid derivatives are the gold standard for the treatment of moderate to severe acute pain, long-term use is problematic. Opioid tolerance rapidly develops, leading to the need for dose increases to obtain the same analgesic effect (32). RgIA4 lacks activity at opioid receptors, and multiple doses of RgIA4, rather than causing tolerance, produced gradual and sustained pain relief.…”

Crosstalk from cAMP to ERK1/2 emerges during postnatal maturation of nociceptive neurons and is maintained during aging

“…However, especially for dynamic processes such as intracellular signaling, additional aspects such as the kinetic, amplitude and pathway connectivity are of central physiological importance. A classic example for the plasticity of intracellular signaling dynamics are changes due to prolonged opioid exposure resulting in a decreased opioid effectiveness or withdrawal-induced pain by an overshoot of the intracellular cAMP levels (Roeckel et al, 2016;Trang et al, 2015). In addition, changes of pathway connectivity are exemplified by the phenomenon of pain priming, where PKA-dependent hyperalgesic signaling switches to PKCε and ERK1/2 involvement (Aley et al, 2000;Dina et al, 2003).…”

Endomorphins: Promising Endogenous Opioid Peptides for the Development of Novel Analgesics

“…Opioid peptides have been used for years in experiments and clinical practices and have been demonstrated to be potent analgesics that are currently widely used to ease patients' pain clinically. However, their side effects of addiction and tolerance are difficult to resolve [35,93].…”

“…However, the accompanied adverse effects of these opioid alkaloids, such as drug dependence, tolerance, respiratory depression and gastrointestinal effects, have always triggered the demand for new alternatives [33][34][35]. The discovery of the EMs can expedite the development of novel analgesics.…”