Opioids as MedicationsPage 6 of 17

4. Morphine-Like Drugs and Synthetic Derivatives

Morphine, meperidine, hydromorphone, oxymorphone, methadone, fentanyl, and large doses of oxycodone (OxyContin) are generally used for severe pain relief. Morphine and full agonists have no limiting effectiveness for pain relief until the side effects prohibit any further increase in dose. Generally, any of the opioids can relieve pain if the correct dose is used, though some have undesirable side effects before full relief is achieved.

Morphine is the standard opioid for comparison; there is strong first-pass metabolism by the liver if it is taken orally, limiting the effective time of analgesia unless a sustained-release form is given. This slow-release form must not be broken up or chewed or an overdose may occur (A to Z Drug Facts, 2008).

Meperidine (Demerol) is very similar to morphine in its actions except that it leads to restlessness instead of sedation and can cause dry mouth and blurred vision from its antimuscarinic receptor effects. It does not have strong antitussive properties and can still lead to euphoric and dependence symptoms. Meperidine has a quicker onset of action than morphine, as rapid as 15 minutes and peaking at 1 to 2 hours, but it irritates tissues and is shorter acting.

Repeated dosing with meperidine can lead to accumulation of the metabolite normeperidine, which has a 15- to 20-hour half-life—compared to only 3 hours for meperidine itself—and can cause tremors, dysphoria, irritability, and possible seizures. Therefore repeated doses for more than 48 hours are not recommended. It is preferred for childbirth because it is short acting and does not depress breathing in the child as much as morphine.

Meperidine should not be combined with patients taking monoamine oxidase (MAO) inhibitors or in those with decreased renal function because severe or lethal complications may occur. The most prominent is an excitatory reaction (“serotonin syndrome”) with delirium, hyperthermia, headache, hyper- or hypotension, rigidity, convulsions, coma, and death. This reaction may be due to the ability of meperidine to block neuronal reuptake of serotonin, resulting in serotonergic overactivity. Single doses of meperidine also appear to be effective in the treatment of postanesthetic shivering and in controlling reactions to immunotherapies such as Herceptin and interferons.

Methadone (half life = 30 hr) and levorphanol (half life = 16 hr) may be used orally for chronic pain. However, their relatively extended half lives can lead to CNS depression of respiration upon repeated doses. Methadone may also have less sedative action. Presumably the longer acting property arises from being bound to tissues extracellularly and then being slowly released over time. Hence withdrawal symptoms may be less severe than with shorter acting opiates like morphine and others, though psychological dependence can be equivalent.

Weak, long-acting MOR agonists like methadone can be used to wean addicts off of morphine and heroin because they would get no rush from a new injection of those while methadone was present, and yet withdrawal symptoms are less severe over time. (See the problems of increasing methadone overdosing and deaths in a later section.)

Tramadol is an oral opiate agonist that is used for rheumatoid arthritis, restless leg syndrome, and fibromyalgia. It can block reuptake of norepinephrine and serotonin and should not be combined with antidepressants, antipsychotics, or MAO inhibitors because of an increased risk of seizures (A to Z Drug Facts, 2008).

Fentanyl (100x morphine) and sufentanil (1000x) are highly potent synthetic phenylpiperidine derivatives, with short acting morphine-like actions, and are often used in anesthesia and in patient-controlled drips. These can give peak analgesic effects within 5 minutes of IV dosing, whereas morphine and meperidine would require 15 minutes. Fentanyl is a very strong opioid, most often used post operatively or for relief of cancer pain. In addition to injectable and patch forms, it also is made as a lollipop for patients to use when there is breakthrough pain even while taking scheduled opioids.

Fentanyl has a relatively small therapeutic index between effective dose and potentially lethal dose. Some patients using the patch (Duragesic transdermal patch) have been overdosed due to increased body temperature with fever and resulting elevated uptake of fentanyl. This has led to depressed respiration and death. Fentanyl has been abused in the illicit drug market, leading to overdose death (CDC, 2008).

Opioids are generally better for nociceptive pain resulting from tissue damage than for neuropathic pain (eg, “phantom limb” pain). Opioid dosage required for relief can vary widely among patients. Generally the dose should be increased until the desired pain relief is accomplished. If side effects become an issue, switching to another opioid is sometimes helpful. For chronic pain treatment, opioids are empirically titrated up to an optimal dose that lasts approximately 4 hours, and then given on a schedule, allowing the patient to skip a dose if it is not needed. Such a schedule works better than waiting for pain to return, when much higher doses may be required for relief. The patient can usually be allowed an option to additional dosing if there is breakthrough pain.

The adverse effects of morphine include CNS respiration depression, sedation, dizziness, nausea, vomiting, itching and constipation. Most serious is the CNS respiratory depression. Tolerance will develop to the emetic and respiration effects, but not the constipation. It is possible to include low doses of amphetamines to combat drowsiness and add stool softeners for the constipation. The transdermal fentanyl patches seem to induce fewer side effects than sustained-release oral morphine. Patients with pulmonary issues (eg, COPD) should be closely monitored for oxygen levels in the early periods of opioid treatment. Patients on multiple medications may be at increased risk for respiratory depression.