1. Introduction
This chapter explores the medicinal chemistry and mechanism of action of substances commonly described as analgesics that are used to alleviate or abolish pain without the loss of consciousness. They act in the central nervous system in contrast to pain-relieving drugs such as aspirin and other non-steroidal anti-inflammatory agents that act at peripheral locations. Their central actions are depressant, but they may be differentiated from general depressants such as anaesthetics and barbiturates in that they mostly influence specific sites that are associated with the pain and the control of respiration.
1.1. Terminology
The term opiate refers to a substance that is derived from opium. Opioid is a broad term used to designate all substances including natural opiates, endogenous opioids (endorphins and enkephalins), semisynthetic and synthetic opioids, that act as ligands (agonists and antagonists) for opioid receptors.
We are no longer using the term narcotic for these agents. In the past, the term narcotic was used to identify strong morphine-like analgesics. It also included any other sleep-inducing drug. Now we refer to these strong morphine-like drugs as opioids.
1.2. Opiates
Opiates are naturally occurring alkaloids derived from the opium poppy (Papaver somniferum). The use of opium and its alkaloids can be traced to the early history of humankind. The first record of opium growth and use dates back to 3400 BC when the opium poppy was cultivated in lower Mesopotamia (Southwest Asia). The ancient Sumerians, who inhabited the southernmost region of Mesopotamia (in modern-day Iraq and Kuwait), referred to the red poppy flowers as “the joy plant “.
Opium (also known as “raw opium”) is the dried latex obtained by making incisions on the green capsules of opium poppy plants. The ultimate origin of the word “opium” is Ancient Greek ópion (“opium”) which is a diminutive form of opós meaning “juice”. The latex (milky sap) of the opium poppy contains up to 80 different alkaloids, including morphine, codeine and thebaine. Morphine, the most active substance in opium, makes up to 12% of the opium latex. It is named after Morpheus, the Greek god of dreams. Morphine is a very powerful painkiller, but it is also very addictive.
1.3. Opioids
Naturally occurring opioid compounds are found in plants (e.g., morphine) and produced in the body (endogenous opioids), where they are widely distributed throughout the central nervous system (CNS). These endogenous compounds are peptides with variable potency and are preferentially bound by different opioid receptors. They have numerous actions including modulation of pain and control of the cardiovascular system, particularly in shock. Although of interest to pharmacologists, endogenous opioids currently have no clinical role. Synthetic and semi-synthetic opioids are widely used clinically, primarily for their analgesic actions, exerting their effect via the same receptors.
1.4. What Is the difference between Opioids and Opiates?
Classically, the term “opiate” refers to alkaloids found naturally in opium (morphine, thebaine and codeine). This also applies to their chemically related derivatives, such as the semi-synthetic alkaloids, like heroin, and prescription narcotics like oxycodone and hydrocodone.
Opioid is a more general term that is used for both natural and synthetic drugs with morphine-like properties, where the chemical structure may differ from that of morphine. So, the term opioid includes any substance, natural, synthetic or semisynthetic that binds to the opioid receptors like fentanyl, hydromorphone, methadone.
Opioids are highly addictive but are also the most clinically effective drugs that are used for relief from pain. Morphine is the gold standard against which all newer opioids are evaluated. Despite a century of opioid research, there are currently no other effective pain therapeutic alternatives that are more effective in controlling pain than morphine. Several side effects resulting from opiate use include tolerance and drug dependence or addiction. Developing powerful new painkillers is a constant battle against side effects, particularly addictions. The discovery and development of safe, potent, non-addictive opioids that can be administered orally remains a significant challenge in medicinal chemistry.
1.5. Mechanism of Action
Opioids are centrally acting drugs that increase our capacity to tolerate pain without causing the loss of consciousness. In general, opioids modulate the incoming pain information in the spinal cord and central sites of the CNS. They act on opioid receptors in the brain and spinal cord. Patients report that pain is still present, but its intensity is decreased, so it no longer bothers them as much.
1.6. Pharmacological Actions of Opioid Agonists
Analgesia. Opioids mimic the actions of endogenous opioid peptides and interact with opioid receptors, to produce analgesia or relief from pain. They temporarily prevent the nerve cells from firing and therefore provide pain relief.
Sedation. Drowsiness, feeling of heaviness and difficulty in concentrating are common. Sleep may occur with relief of pain, although they are not true hypnotics. Some opioids are excellent antitussives or cough suppressants. This action is not related to analgesia.
Constipation. Some opioids can be used to relieve diarrhea or their action can result in constipation when opioids are used for pain relief.
Anaesthesia. Opioids can be used as anesthetics, with careful titration of the dose. Patient’s ventilation (respiration) must be supported mechanically due to respiratory depression.