Opioids are a group of natural, synthetic, or semisynthetic chemicals that interact with opioid receptors on nerve cells in the body and reduce the intensity of pain signals. They are one of the most prescribed medications among medical professionals and are used ubiquitously in a variety of settings. Their effectiveness has resulted in opioids becoming a target for recreational abuse leading to a worldwide public health burden. Data obtained from the CDC suggest that, in the past 5 years, more than 17% of Americans had at least one opioid prescription filled, with an average of 3.4 opioid prescriptions dispensed per patient.¹ Natural and synthetic opioids continue to be a mainstay in medicine for the foreseeable future, used in every facet of medicine, and as such, it is imperative that providers understand the utility of this drug as well as its global effects.

The terms opioids and opiates are often used interchangeably, though there is a distinction. For completeness, the term opiate analgesic primarily describes naturally occurring opium products such as heroin, morphine, and codeine, obtained from the juice of the poppy. An opioid is an all-encompassing term that includes natural or synthetic compounds that act like morphine and binds to the same receptors.

Organic opioids were first identified by the Sumerians in Mesopotamia around 3400 BC. This was the first group to cultivate the poppy plant, calling it Hul Gil or “joy plant,” which subsequently led to the isolation of opium for its euphoric effect. The opium poppy is botanically classified as Papaver somniferum. The genus is named after a Greek noun for poppy, the species derived from a Latin word meaning “sleep inducing.” Soon after this isolation, its use became widely spread throughout Europe, the Middle East, and North Africa. In the 7th century BC, doctors considered opium a cure for almost every ailment, sometimes mixing it with licorice or balsam.²

Morphine is commonly considered to be the archetypal opioid analgesic and the standard to which all other opioids and opiates are compared. Morphine was first isolated from opium in 1806 by Friedrich Sertürner, a German scientist who studied alkaloid chemistry and was able to describe the isolation, crystallization, and pharmacological properties of what is considered the first modern opioid.³ He named the pure alkaloid after Morpheus, the Greek god of dreams. This discovery, in conjunction with the invention of hypodermic needles by Charles Pravaz and Alexander Wood, led to widespread clinical use of morphine.⁴

Four chemical groupings of natural, synthetic, and semisynthetic opioid alkaloids have been characterized as derivatives from the parent P somniferum. These groupings are morphinan, phenylpiperidine, diphenlyheptane, and benzomorphan derivatives.

Morphinan derivatives, also known as phenanthrenes, include the most common opioids and are the most widely used among practitioners. This group includes oxycodone, hydrocodone, hydromorphone, morphine, codeine, nalbuphine, buprenorphine, and butorphanol. Phenylpiperidine derivatives include fentanyl, alfentanil, sufentanil, and meperidine. This group is also widely used, though in a smaller clinical setting when compared to morphinan derivatives. Diphenlyheptane derivatives include propoxyphene and methadone. Benzomorphan derivatives consist of only pentazocine. This drug is a partial agonist that is characterized by high incidence of dysphoria and is not commonly used in clinical practice.

Since pain is a sensory and emotional experience, the transmission of pain is multifactorial and complex.⁵ However, in the simplest depiction, pain is transmitted as a noxious stimulus along a three-neuron system that originates at the periphery and terminates at the cerebral cortex. The first is a nociceptor, which is a primary afferent neuron with a peripheral terminal at the site of stimulation. The second is a neuron in the spinal cord or dorsal horn that receives input from the nociceptor and then projects to the thalamus. The final, third neuron projects from the thalamus to the sensory cortex.⁶,⁷ The integration of this noxious stimuli in the supraspinal region then leads to the perception of pain, which has many components—sensory, emotional, and physiologic.

Noxious sensations can be categorized into two components: a fast, sharp, and well-localized sensation, which is conducted by A-δ fibers, and a slow, dull, poorly localized sensation, which is conducted by C fibers.

Opioids inhibit the sensation of nociceptive pain by blocking the transmission at every step along this pathway. They do so by binding to a variety of G-coupled receptors that in turn attenuate nociceptive transmission.

Clinically important effects of opioids are mediated by three receptors known as µ, κ, and δ. The nomenclature has since evolved, and internationally, these receptors are known as MOP, KOP, and DOP. A fourth receptor, NOP, may also be involved in pain processing. The three classes of receptors share significant gene sequence homologies and belong to the rhodopsin family of GPCRs.⁸ These receptors in humans have been mapped to chromosome 1p355-33 (DOP), chromosome 8q11.23-21 (KOP), and chromosome 6q25-26 (MOR).⁹ These opioid receptors are widely distributed and are found in neuronal cells at the periphery, dorsal horn of the spinal cord, brainstem, thalamus, and cortex, as well as nonneuronal cells in the GI tract. All opioid receptors couple to G_i/G_o proteins—this binding of an agonist receptor causes membrane hyperpolarization. Immediate opioid effects are mediated by inhibition of adenylyl cyclase and activation of phospholipase C. These intracellular events inhibit voltage-gated Ca²⁺ channels causing downstream reduction of neurotransmitter release from presynaptic terminals and activate inwardly rectifying of K⁺ channels, which hyperpolarizes and inhibits postsynaptic response to excitatory neurotransmitters.¹⁰

The clinical effects of a particular opioid depend on which receptor that it binds (Table 31.1). Opioids are often characterized by the differences in affinity for specific receptors and their functional response. MOP is ubiquitous and seen throughout the CNS. All MOP receptors are encoded by a single gene, OPRM1, found on chromosome 6q24-a25. There have been over 20 MOP receptor variants that have been identified, which may account for the variability in efficacy and toxicity with MOP agonists.¹¹ The effects of MOP involve analgesia, euphoria, respiratory depression, sedation, tolerance, physical dependence, decreased gastrointestinal motility, biliary spasm, and miosis. DOP receptors are widely distributed, and they are
primarily responsible for mediating the analgesic effects of endogenous opioids. KOP receptors share several effects with MOP, including analgesia, sedation, and respiratory depression. The KOP receptors have been further divided into several subclasses that are relevant to opioid pharmacology. κ₁ receptor mediates spinal analgesia, whereas κ₃ mediates supraspinal analgesia, sedation, and respiratory depression.¹² NOP is a relatively newer class of receptors that act in a similar fashion to the classical receptors. NOP receptors are thought to effect locomotion, stress, anxiety, feeding, learning and memory, reward/addiction, and urogenital activity. It is believed that the NOP system may be involved in development of tolerance to opioids. The characterization of this receptor is ongoing and may prove useful in reducing tolerance and providing analgesia in the future.¹³