Opioids

Medical Uses

Opium contains 10% morphine but also other opiate alkaloids, such as thebaine and codeine. Morphine was first isolated from opium by Serturner in 1804 and named after Morpheus, the God of Dreams, or Morphina, the God of Sleep – both very appropriate reflections of opium’s effects. Codeine was first isolated from opium in 1832 by Robiquet and subsequently used in the United States as a tonic for various problems and ailments. It is still the most widely prescribed legal opioid used largely for analgesic, antitussive, and anti-diarrheal effects. Thebaine is stimulatory instead of sedative and at higher doses produces convulsions. Thebaine was mainly used to produce semi-synthetic derivatives of opiates, such as naloxone (an opioid antagonist) and oxycodone (a powerful opioid agonist; Figure 5.2). Heroin (diacetylmorphine) was developed by the Bayer Company in 1898 as an effective cough suppressant with alleged stimulant action on the respiratory system. Although heroin does appreciably inhibit the cough reflex, the latter assertion of a stimulant-like effect was later proven false (Figure 5.3). As mentioned above, another well-known (and often undesirable in the context of pain management) effect of opioids is their anti-diarrheal effects, which in the management of chronic pain must also be managed with the use of other drugs that help prevent or reverse the blockade of gastrointestinal motility.

FIGURE 5.2 The four sources of opioids. (1) Opium is the natural source of opiates, such as morphine, codeine, and thebaine. (2) The semi-synthetic opioids are derivatives of the natural opiates. (3) The synthetic opioids are not derived from natural opiates. (4) Endogenous opioid peptides are found in the body and brain.

However, the most common indication for the prescription of opioids is their unmatched effectiveness in pain relief (Box 5.2). Opioids are the most powerful and effective drugs known to man for the relief of pain. Pain relief from morphine at a standard dose of 10 mg administered intramuscularly or subcutaneously lasts up to 3–4 h. Opioid analgesia has been described as the selective suppression of pain without effects on other sensory modalities at reasonable analgesic doses. Opioid analgesia also distinguishes between different types of pain. Opioids have minimal effects on the initial sharp sensation produced by noxious stimuli but are very effective against the dull continuous ache that continues after a noxious stimulus. Presumably, this distinction has survival value. The selective suppression of continuous pain by endogenous opioids allows for relief from the pain of a previous injury but does not eliminate one’s awareness of the immediate danger of a new injury. Opioids are less effective in reducing the neuropathic pain that results from nerve injury. Perhaps more importantly for the neurobiology of addiction, opioids also effectively reduce the “affective dimension of pain” (for further reading, see Gutstein and Akil, 2001).

FIGURE 5.3Advertisements from the Bayer Company and Martin M. Smith & Co. Ltd. for the use of heroin for the treatment of cough, circa early 1900s.

BOX 5.2

TYPES OF PAIN

Somatic Pain

Also called “nociceptive pain,” somatic pain refers to the sensation caused by peripheral nerve fiber stimulation. Such pain can be further classified as either mechanical or thermal.

Neuropathic Pain

Neuropathic pain can result from injury to the nerves of the central nervous system. The pain can be described as a burning sensation or “pins and needles,” such as a person experiences when their leg “falls asleep.” Dysesthesia is the global term used to describe such abnormal sensations. Neuralgia refers to pain that occurs in nerves without specific stimulation of nociceptors. Allodynia is another form of neuropathic pain, referred to as pain elicited by normally innocuous stimuli.

Affective Dimension of Pain

The moment-to-moment unpleasantness of pain is made up of emotional feelings that pertain to the present or short-term future, such as distress or fear.

Opioids also produce analgesia when administered into the periphery or at local sites, and opioid receptors are present on peripheral nerves. Opioids are commonly administered epidurally (into the outermost space of the spinal canal) for the management of obstetric pain during delivery. Both the epidural and intrathecal (under the arachnoid membrane that surrounds the brain) routes of administration have been used for chronic pain states, such as lower back pain, neuralgia, and limb pain. With intrathecal administration, the drug can access cerebrospinal fluid and thus avoid the blood-brain barrier. With epidural administration, opioids bind to opioid receptors in the spinal cord and produce analgesia without causing impairments in motor or sensory function. Drugs with high selectivity for the μ opioid receptor and high lipid solubility, such as fentanyl, are taken up rapidly into the spinal cord and have a fast onset of action.

Opioids are often used to relieve pain during general anesthesia. However, they also are a component of “balanced anesthesia,” in which a balance of agents is used to produce the different components of anesthesia, including analgesia, amnesia, muscle relaxation, and the abolition of autonomic reflexes. Currently, fentanyl and its congeners alfentanil and remifentanil are used as components of balanced anesthesia because of their rapid onset of action. The inclusion of an opioid into general anesthesia can also reduce preoperative pain and anxiety, decrease adverse responses to manipulations of the airways, lower the requirements for inhaled anesthetics, and provide immediate postoperative pain relief.

Patient-controlled analgesia is a method of opioid administration in which the patient can carefully titrate the rate of opioid administration to meet their individual pain relief needs. Although such titration can be achieved with oral dosing, specifically designed infusion pumps can deliver a continuous infusion with bolus doses by the intravenous, subcutaneous, or epidural routes. The pumps are programmed to the needs of the patient, with limits set to prevent overdose. This method of delivery can provide a consistent level of analgesia and is associated with greater patient compliance.

Table 5.1 shows the equivalent doses of commonly prescribed opioids required to produce analgesia similar to a standard 10 mg dose of morphine. Numerous natural and synthetic opioids are available for mild to moderate pain relief. Codeine, a natural component of opium, is the most commonly used opioid analgesic for the management of mild to moderate pain and is often combined with aspirin or acetaminophen. It is significantly less potent than morphine. Oxycodone (oxycontin) is a synthetic derivative of morphine that is used for the management of mild to moderate pain and is nearly equipotent with morphine when given orally and slightly more potent than morphine via the intravenous route.

The use of prescription opioids for pain is steadily increasing in the United States, paralleled by an increasing prevalence of chronic pain syndromes. The prevalence of prescription opioids in the United States, according to the Institute of Medicine 2011, is estimated to be 70–116 million. As will be seen below, in some individuals with chronic pain, the use of chronic opioids leads to opioid-induced hyperalgesia, adding to the difficulty of the differential diagnosis of chronic pain and opioid withdrawal.

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