Daniel X Freedman R N Pechnick

MORPHINE Morphine is a major component of OPIUM, a product of the poppy plant (PAPAVER SOMNIFERUM or P. album). Named after Morpheus, the Greek god of sleep, morphine is a potent ANALGESIC (painkiller) that is widely used for moderate to severe PAIN. Morphine is one of approximately twenty ALKALOIDS in opium; it was first purified in 1806 and, by the mid-1800s, pure morphine was becoming widely used in medicine. At approximately the same time, the hypodermic needle and syringe was developed, which permitted the injection of the drug under the skin (subcutaneous, S.C.), into muscles (intramuscular, I.M.), or directly into the veins (intravenous, I.V.). Together, these routes of administration are termed paren-teral. Injections provide rapid relief of pain and can be used in patients who are unable to take medications by mouth. These advantages led to the wide use of morphine injections during the American Civil War (1861-1865). At that time, the intense euphoria and addictive potential of these agents following injections was not fully appreciated, leading to the addiction of a large number of soldiers. Indeed, morphine was not illegal and was sold over the counter; ADDICTION soon became known as the Soldier's Disease.

Since that time, a major objective of pharmaceutical companies has been to develop, for medication purposes, a nonaddictive analgesic with the potency of morphine. The concepts of PHYSICAL DEPENDENCE and addiction were not clearly differentiated until the late twentieth century, and it is likely that most of those early addicts were attempting to prevent the onset of WITHDRAWAL symptoms. Today very few patients become addicted to opiates, despite the fact that with continued administration all will become physically dependent — this may reflect our better understanding of the drugs plus our ability to take a patient off medications without precipitating withdrawal symptoms.

Morphine produces a wide variety of actions, some desired and others not. The definition of a desired action and a side effect depends on the reason for using the drug. For example, opiates such as morphine can be used to treat diarrhea— but their constipating actions are usually considered an undesirable side effect when they are used to treat pain.

Clearly, the control of pain remains the most important use for morphine. Morphine and other OPIATES relieve pain without interfering with traditional sensations. Patients treated with morphine often report that the pain is still there but that it no longer hurts. Morphine works through mu opiate Receptors located both within the brain and the spinal cord. Morphine has a number of other actions as well. Its ability to constrict the pupil is one of the most widely recognized signs of opiate use. In addition, morphine produces sedation and, at higher doses, morphine will depress respiration.

Figure 1

Morphine

Very high doses of morphine will stop breathing entirely—a common occurrence in overdoses.

Morphine also has a major influence upon the gastrointestinal tract, which is the basis for its antidiarrheal effect. Here, morphine decreases the motility of the stomach and intestine, through local actions on the organs themselves, as well as through control systems located within the brain and spinal cord. Other systems can be affected as well. Morphine produces a vasodilation, in which the peripheral blood vessels are relaxed. This can lead to significant drops in blood pressure when a person shifts from a lying to a standing position as the blood is pooled in the legs. This ability to pool blood in relaxed blood vessels can be used clinically to treat conditions such as acute pulmonary edema, an accumulation of fluid within the lungs, which occurs in acute myocardial infarctions (heart attacks). Increasing the capacity of the vascular system by relaxing the blood vessels permits the reabsorption of the lung fluid. Finally, morphine and similar drugs, such as CODEINE, are also effective agents in the control of coughing.

All these effects of morphine can be easily reversed by Antagonists. Naloxone is the most widely used antagonist. Given alone, it has virtually no actions; however, low doses of naloxone are able to block or reverse all the actions of morphine described above.

Morphine is given either by mouth or by injection. Oral administration is associated with a significant metabolism of the drug by the liver, explaining its lower potency as compared to that attained by injections. From three to six times more morphine must be taken by mouth to produce the same effects as an injected dose. Thus, higher doses are needed when giving the drug orally. Morphine injections can be given either intramuscularly, sub-cutaneously, or intravenously. Continuous infusions are also becoming more common, but their use is restricted to physicians expert in the treatment of pain. Morphine has a relatively short halflife in the body, around two hours, and it is usually given to patients every four to six hours. It is extensively metabolized. In the late 1980s, it was discovered that one of these metabolites, morphine-6^-glucuronide, is very potent, far more potent than morphine itself. The importance of this compound with a single morphine dose is probably not great; however, with chronic dosing, the levels of mor-phine-6^-glucuronide in the blood actually exceed those of morphine—so this metabolite may be responsible for most of morphine's actions. Since this metabolite is removed from the body by the kidneys, special care must be taken when giving morphine to patients with kidney problems.

One common problem associated with morphine is nausea. This is difficult to understand, since nausea does not occur in all patients and often is seen with one drug but not others. This lack of consistency raises questions about whether it is a specific receptor-mediated action or whether it may be a nonspecific side effect.

With chronic use, morphine has a progressively smaller effect, a phenomenon termed TOLERANCE. To maintain a constant action it is necessary to increase the dose. Along with tolerance, morphine also produces physical dependence. Physical dependence (physiological dependence; neuroadaptation) develops as the body attempts to compensate for many of morphine's actions. As long as a person continues to receive the drug, no symptoms are noted. Abrupt cessation of the drug or the administration of an antagonist, such as naloxone, produces a constellation of symptoms and signs termed the withdrawal syndrome. Early symptoms include a restlessness, tearing from the eyes and a runny nose, yawning, and sweating. As the syndrome progresses, one sees dilated pupils, sneezing, elevations in heart rate and blood pressure, and gooseflesh—which is responsible for the term ''cold turkey. ' Cramping and abdominal pains are also common.

Physical dependence (or neuroadaptation) is a physiological response to repeated dosing with morphine and is seen in virtually all patients. Physical dependence, however, is not the same as addiction (drug dependence). Drug dependence (addic tion) is defined as drug-seeking behavior, whereas physical dependence is simply a physiological response to the medication. While addiction is common among drug abusers, it is rare when morphine is used for appropriate medical conditions. The reasons for this difference are not clear, and they remain a major issue in understanding and treating morphine addiction.

(SEE ALSO: Addiction: Concepts and Definitions; Diagnostic and Statistical Manual; Opiates/Opi-oids; Opioid Complications and Withdrawal)

BIBLIOGRAPHY

Reisine, T., & Pasternak, G. (1996) Opioid analgesics and antagonists. In J. G. Hardman et al. (Eds.), The pharmacological basis of therapeutics, 9th ed. (pp. 521-555). New York: McGraw-Hill.

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