Overview Of Opioid Medications

Opioids are medications that are derived from the opium poppy, Papaver somniferum. They have a long history of pain relief and have been used in various forms, such as elixirs, potions, and smoking substances, since the time of the Sumerians, when the poppy was depicted in art as "the plant of joy" (Fine & Portnoy, 2007). Reports from early Greek, Egyptian, and Roman societies described the fact that many of the leaders and everyday citizens used opium for pain relief. In the 16th century, the use of laudanum, an opium-derived elixir, was common for a wide variety of pain complaints. It was during this time that dependence and tolerance were noted to be occurring in laudanum users.

The term opioid or opiate denotes a class of medications that are derived from the latex sap of the P. somniferum or created as analogues to these natural substances. Opium has a two-sided history: one as a potent analgesic and the other as a recreational drug. For example, it was smoked for its euphoric effect in the opium dens of China and also used for pain relief. Early herbalists recognized the pain-relieving potential of opium and used it to treat many different types of pain in their patients.

During the same period, large amounts of opium were traded between the Chinese and the British. The supply was high and demand for the product was just as great, leading to wars and infighting over the use of opium to balance trade. Morphine was first isolated in 1895 in Germany, where the medication was thought to be useful as a cure for opium addiction (Fine & Portnoy, 2007). The development of the hypodermic syringe in the mid-19th century gave medical practitioners another route for delivering opioid medications, which they injected directly into the site of the pain.

By the 20th century, opioid use not only was seen as beneficial for treating pain but also had become problematic as opioid abuse increased. The United States passed the first two acts for controlling the use of these substances: The Pure Food and Drug Act (1906) and the Harrison Narcotics Act (1914). These were the first two attempts at controlling the use and prescribing of opioid substances. As late as 1970, the Federal Controlled Substances Act provided standards for monitoring, manufacturing, prescribing, and dispensing of opioids and created the five-level division of controlled substances that we use today.

In general, opioids are some of the best medications we have to control pain. They come in various formulations, and they have a good profile for adverse side effects when compared with other medication types.

Natural derivatives of the opium include morphine, codeine, and heroin. Synthetic analogues, such as fentanyl (Sublimaze) and meperidine (Demerol), were developed much later as attempts to perfect compounds for better pain relief. Several things that these compounds all have in common are the following:

■ They activate by binding sites in the body called mu receptors to produce analgesia. Mu receptors are found in many places in the body, including the brain and spinal column neurons.

■ Their main action is analgesia.

■ Side effects, such as sedation, constipation, and nausea, are common with all members of the drug class.

■ They all have the potential for addiction.

The Various Forms of Opioids

Some of the opioids are used in the natural form, such as morphine and heroin.

Other natural opium alkaloids include codeine, noscapine, papaverine, and thebaine. These alkaloids can be further reduced into more common analgesic compounds. The alkaloid thebaine is used to produce semisynthetic opioid morphine analogues, such as oxycodone (Percocet, Percodan), hydromorphone (Dilaudid), hy-drocodone (Vicodin/Lortab), and etorphine (Immobilon). Other classes of morphine analogues include the 4-diphenylpiperidines: meperidine (Demerol), diphenylpropylamines, and methadone (Dolophine). Each of these compounds was developed to either increase analgesic effect or reduce the potential for addiction.

Although all of the opioid substances can be classed as pain relievers, their potency varies. Etorphine is one of the most potent of the analogue compounds, with very small amounts providing a large effect. Every member of the morphine group has one chemical similarity. There must be a piperidine ring in the chemical configuration, or a greater part of the ring must be chemically present to be classed as a morphian.

The main binding sites for opioids are the mu receptors (Holden, Jeong, & Forrest, 2005). These receptors are found in the following:

■ Periaqueductal gray matter

■ Spinal cord substantia gelatinosa (Fine & Portnoy, 2007)

Other secondary binding sites include the kappa and delta sites. Kappa sites are found in the brain's hypothalamus, periaqueductal gray matter, and claustrum, and in the spinal cord substantia gelatinosa (Fine & Portnoy, 2007). The delta receptors are located in the pontine nucleus, amygdala, olfactory bulbs, and deep cortex of the brain (Fine & Portnoy, 2007). Recently, an opioid receptorlike site was discovered and called opioid receptor-like 1 (Figure 4.1). The activity at this site is thought to be related to central modulation

of pain but does not appear to have an effect on respiratory depression (Fine & Portnoy, 2007).

When an opioid is introduced into a patient's body, it looks for the binding site that conforms to a specific protein pattern that will allow the opioid to bind to the receptor and create analgesia, an agonist action. At one time, the binding action for opioids was felt to be a simple lock-and-key effect: Introduce the medication; medication finds the binding site and binds, creating analgesia. Today, we know that the process is much more specific and is more sophisticated than a simple lock-and-key effect.

Once the opioid molecule approaches the cell, it looks for a way to bind. On the exterior of each cell are ligands, or cellular channel mechanisms, connecting the exterior of the cell with the interior and conveying the opioid molecule into the cell. The ligands are affiliated with the exterior receptor sites and can contain various G proteins. These G proteins couple with the opioid molecule and mediate the action of the receptor (Fine & Portnoy, 2007). "One opioid receptor can regulate several G proteins, and multiple receptors can activate a single G protein" (Fine & Portnoy, 2007, p. 11). As efforts progress to better identify the process, more than 40 variations in binding site composition have been identified (Pasternak, 2005). These differences explain some of the variations in patient response to opioid medications.

The body also has natural pain-facilitating and pain-inhibiting substances. These include the following:

■ Facilitating: substance P, bradykinin, and glutamate

■ Inhibiting: serotonin, opioids (natural or synthetic), norepinephrine, and gamma-aminobutyric acid

When these substances are activated or blocked, pain can be relieved or increased. These more complex mechanisms are difficult to tease out, and trying to link them to analgesia and opioid effect can be misguided. More information on pain-facilitating and pain-inhibiting substances can be found in Chapter 1.

Types of Opioid Medications

Opioid medications are very versatile in that they can be given as a stand alone medication, for example, codeine, or combined with another type of nonopioid medication, such as an NSAID (e.g., ibu-profen [Combunox] or acetaminophen [Tylenol #3 or Percocet]). Some of the medications are elixirs, such as morphine (Roxanol), and others have a suppository form, such as hydromorphone (Dilau-did). Because the morphine elixir form can be very bitter, adding a flavoring available at most pharmacies can help the patient tolerate the taste of the medication.

The duration of the oral short-acting preparations is usually listed as 4 to 6 hours, but each patient has an individual response and ability to metabolize medications. Most of the combination medications are considered short acting, and the combination of another type such as NSAIDs or acetaminophen, of medication limits the amount of medication that can be taken in a 24-hour period. Those that are combined with acetaminophen follow the recommended dose for daily acetaminophen use to 4,000 mg/day maximum (American Pain Society [APS], 2008).

Other medications, especially those on the third level of the World Health Organization analgesic ladder, have extended-release (ER) formulations. These ER formulations not only make the medication a pure opioid agonist but also extend the dosing time to 12 to 24 hours (e.g., ER morphines [MS-Contin, Avinza, Kadian] or ER oxycodone [Oxycontin]) and the new formulation of hydromorphone ER (Exalgo). These ER medications are particularly helpful for patients in whom pain is present throughout the day, such as patients with chronic pain and patients with cancer. These ER medications are not designed to be used in patients who are opioid naïve (patients who have not been taking opioid medications on a daily basis), but for those who have been taking the short-acting medications on a daily basis to relieve their pain (opioid-tolerant patients).

Some long-acting opioid medications, such as the fentanyl patch (Duragesic), have specific short-acting medication requirements before they can be used (e.g., before using Duragesic 25 mg, the patient must have been using Dilaudid 8 mgs per mouth daily, or oxycodone 30 mgs per mouth, or morphine 60 mgs per mouth for 2 weeks prior). Every patient who uses an ER opioid medication for pain should have a short-acting medication to use for breakthrough pain that occurs with increased activity or end-of-dose failure that allows pain levels to increase (APS, 2008) (Table 4.1).

No matter what type or form of opioid medication is being considered for use, the health care prescriber should be aware of the risks and benefits of each medication and weigh the options carefully. A full history and physical and risk assessment for opioid therapy should be performed.

Short-Acting Combination Medications

Short-acting pain medications come in a wide variety of types. Some are combined with acetaminophen or other nonopioid medications, and others are opioid medications, such as oxycodone, that only last for several hours at the recommended doses. For most patients with an acute injury, such as surgery, a short-acting

Table 4.1 ■ Common Opioid Medications

Common Opioid Medications—Short acting

Medication name

Generic name/ combination name

Usual starting dose—Adidts

Maximum dose


Tylenol #3

30 to 60 milligrams by mouth every 4-6 hours

12 tablets in a 24 hour period Limited by acetaminophen—available as an elixir


Lortab Vicodin

5 to 10 milligrams by mouth every 4-6 hours 5 to 10 milligrams by mouth every 6 hours

Limited by acetaminophen dose



5 milligrams every 6 hours

Limited by acetaminophen dose


Ultram Ultracet

25 milligrams by mouth in AM

Maximum 400 milligrams per day Limited by acetaminophen dose



50, 75, or 100 milligrams every 4-6 hours

No more than 700 milligrams on day 1 and thereafter 600 mg maximum



10-20 milligrams by mouth every 4 to 6 hours

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