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RESPIRATORY DEPRESSION

It is generally believed that the most common life-threatening complication of opioid use, whether therapeutic or illicit, is respiratory depression (loss of the ability to breathe automatically). Probably the most important action of morphine-like drugs in producing respiratory depression is the lessening of the sensitivity and responsivity of the brain's medullary respiratory center to carbon dioxide (CO₂—the metabolic waste that circulates in the blood, derived from carbonic acid during animal respiration). Therefore, CO₂ becomes an inefficient respiratory stimulant, and automatic breathing ceases.

Administering a specific opioid ANTAGONIST such as NALOXONE to patients with severely depressed respiration frequently produces a dramatic increase in the rate of respiration and the volume of air taken in per breath. This occurs when a partial or completely resensitized respiratory center is confronted with high brain levels of CO₂. When the brain CO₂ levels are dissipated as a consequence of the evoked excessive rate and volume of breathing (hyperpnea), the minute volume (the volume of air breathed per minute) decreases. Yet when brain levels of the antagonist decrease, the respiratory depressant action of the opioid may assert itself again. Naloxone is a relatively short-acting antagonist. Patients who, for example, have received an overdose of long-acting opioids (e.g., METHADONE) have experienced a fatal respiratory depression following successful treatment with naloxone.

TOLERANCE AND PHYSICAL DEPENDENCE

Another group of complications associated with chronic use of opioids is the development of tolerance and dependence.

Tolerance.

The most common concept of TOLERANCE to opioid drugs is that following chronic administration of a drug, its effects are diminished. Several mechanisms have been demonstrated to be involved in the development of tolerance to drugs, and these include (1) the induction of drug-metabolizing enzymes; (2) the development of coping strategies; (3) the exhaustion or depletion of NEUROTRANSMITTERS; and (4) an alteration in the number of active and inactive RECEPTORS. These mechanisms have, by and large, failed to provide adequate explanations for tolerance to opioid drugs. This may stem in part from the complexity of the results of chronic administration of opioids, the involvement of multiple mechanisms, and the influence of the dose, route, and frequency of drug administration.

Opioids, for example, alter the functioning of some body homeostats, and apparent tolerance is related to the establishment of new equilibrium conditions. This is clearly evident in respiratory depression, where opioids depress both the sensitivity and the reactivity of the brain-stem respiratory CO₂ homeostat, causing CO₂ to be a less effective respiratory stimulant. Yet when CO₂ accumulates because of depressed respiration, the increasingly higher concentrations will cause stimulation of respiration to the degree that the altered homeostat dictates. The ability of opioids to constrict pupils is dose-related, and patients receiving opioids frequently have miosis—near-maximally constricted pupils; hence, it is difficult to determine if tolerance develops to opioids' miotic effect. This has given rise to the commonly accepted view that tolerance does not develop to the miotic effects of opioids.

In former opioid addicts, morphine-like drugs produce dose-related feelings of enhanced self-image, of being more efficient and effective, and of well-being. These related subjective states form the essence of opioid-induced euphoria, which is produced in patients who are plagued by feelings of inadequacy. This can be quantitatively measured using the Morphine-Benzedrine Group scale of the Addiction Research Center Inventory.

Tests in many normal subjects (nonabusers) who are not suffering from pain indicate that opioids do not produce euphoria—but in sufficiently large doses instead produce feelings of apathy and ineffectiveness, which can be dispiriting (dysphoric). When opioids are administered chronically to addicts, the subjective effects they produce change from feelings of well-being to feelings of being withdrawn, tired, and weak. With regard to these effects of chronic opioid administration, they are not simply diminished but rather changed.

The development of tolerance can be a problem when opioids are used in the treatment of pain. Although some degree of tolerance to ANALGESIC effects is expected when opioid drugs are used repeatedly, in practice there is a great deal of variability among patients. Some patients with CANCER pain appear to derive satisfactory relief from the same dose of MORPHINE or similar drugs over a period of many months. For these patients, a need to increase the dose can be a signal that the disease is progressing. Other patients with terminal disease can develop remarkable tolerance. There are reports of patients who have been given the equivalent of 1000 milligrams of morphine per hour intravenously. This is an impressively large dose, since the usual starting therapeutic doses of morphine are 10 to 15 milligrams by injection every 4 to 6 hours, and doses of more than 60 milligrams by injection can cause potentially fatal respiratory depression in nontolerant individuals. It is not usually of much benefit to change to another opioid that acts at the same receptor. For example, morphine acts at the mu-opioid receptor. When tolerance develops to morphine, other opioids acting at mu receptors will be less effective, a phenomenon referred to as "cross-tolerance."

Physical Dependence/Withdrawal.

Closely related to the phenomenon of tolerance is the phenomenon of physical dependence. Subjects given repeated doses of opioid agonists exhibit a syndrome when the drug is withheld or when the subject is administered an opioid antagonist. The resulting group of signs and symptoms is called the WITHDRAWAL or precipitated abstinence syndrome; subjects who exhibit an abstinence syndrome are termed physically dependent on the opioid. The degree of physical dependence and the intensity of the abstinence syndrome are related to the dose of the opioid agonist chronically ingested. In general, the intensity of all signs and symptoms covary together.

The abstinence syndrome includes restlessness, weakness, chills, body and joint pains, gastrointestinal cramps, anorexia (loss of appetite), nausea, feelings of inefficiency, and social withdrawal. Signs of abstinence include activation of the autonomic nervous system, lacrimation (tearing eyes), rhinorrhea (running nose), piloerection (gooseflesh), tachypnea (rapid breathing), mydriasis (dilated pupils), hypertension (high blood pressure), tachycardia (rapid heart beat), muscle spasms, twitching, restlessness, vomiting, and diarrhea. The waves of gooseflesh that occur during severe opioid withdrawal reminded some observers of the look of a plucked "cold turkey," a term that has come to be used not only for any abrupt discontinuation of a drug, but also for sudden cessation of any habit or pattern of behavior. The twitching and kicking movements of the lower extremities that can occur during opioid withdrawal have given the English language another widely used term, "kicking the habit," to denote the process of giving up any pattern of behavior or drug use.

The time of onset of opioid abstinence depends on the length of activity for the dependence-producing opioid. The abstinence syndrome of subjects dependent on morphine or HEROIN is well developed within 24 hours after the last dose of the opioid, peaks after 48 hours of abstinence, and gradually subsides thereafter. Signs of abstinence in patients dependent on METHADONE begin to emerge 24 to 48 hours after the last dose and may not peak for 2 weeks.

After this early abstinence syndrome subsides, a protracted abstinence syndrome emerges. The protracted abstinence syndrome becomes manifest 5 to 10 weeks after acute or early withdrawal in humans. It differs from the early abstinence syndrome in some ways but not in others. In subjects who were dependent on morphine or methadone, protracted abstinence is characterized by the following signs: a modest hypotension (low blood pressure), bradycardia (low heart rate), hypothermia (lower than normal body temperature), miosis (small, constricted pupils), and tachypnea. Other signs of protracted abstinence may include an inability to concentrate and a decrease in fine-motor control. Symptoms associated with protracted abstinence in patients who were dependent on methadone include feelings of tiredness and weakness, withdrawal from society, inefficiency, decreased popularity and competitiveness, and loss of self-control. Patients withdrawn from methadone have also exhibited a significant elevation of the Sc (schizophrenia) scale of the MINNESOTA MULTIPHASIC PERSONALITY INVENTORY (MMPI). This elevation of the Sc scale may be related to feelings of social withdrawal that patients in protracted abstinence experience. Protracted abstinence persists for at least 25 weeks after withdrawal. Protracted abstinence following addiction to morphine has also been demonstrated in rats and in dogs.

The patterns of abstinence and time course of symptoms described above are those seen when opioid drugs that have been used for weeks or months are discontinued. However, opioid withdrawal can also be observed when a drug-dependent person is given an opioid antagonist (a drug such as naloxone that competes with opioid agonists for the opioid receptor). In a matter of minutes, this will produce a precipitated abstinence syndrome that can be severe, with vomiting, cramps, and diarrhea. This precipitated abstinence is usually brief, however, because as soon as the antagonist is metabolized (usually less than an hour for naloxone), the opioids still in the body can again attach to the opioid receptors and suppress the abstinence syndrome.

The biological mechanisms that are responsible for the development of opioid physical dependence are set into motion with the very first doses of an opioid drug. If volunteer subjects are given standard doses of morphine (15 to 30 mg) and then, after an interval varying from 6 to 24 hours, they are given naloxone, they report nausea and other feelings of dysphoria and exhibit yawning, dilated pupils, tearing, sweating, and runny nose. Changes in endocrine levels are also seen that are in the same direction, although not as extreme, as those seen when chronically administered opioids are abruptly discontinued.

TREATMENT OF OPIOID WITHDRAWAL (DETOXIFICATION)

The opioid withdrawal syndrome varies in severity depending on the amount of opioid used and the duration of use. For the average user of illicit opioids, withdrawal is rarely severe because the amount of drug used typically is not high. The withdrawal syndrome from such a level of use can be uncomfortable, but it is not life-threatening in otherwise healthy individuals. However, death can occur if severe withdrawal is left untreated in individuals who are weakened by other medical conditions.

The process of treating someone who is physically dependent so that acute withdrawal symptoms are controlled and the state of physical dependence is ended is usually referred to as detoxification. For opioid drugs, this process can be managed on an ambulatory (outpatient) basis or in a hospital or other residential (inpatient) setting. The most common approach to easing the severity of opioid withdrawal is to slowly lower the dose of opioid over a period of days or weeks. However, in the United States, if the drug has been heroin, a substitution technique is used instead. Since virtually all opioids that are abused act as AGONISTS at the mu-opioid RECEPTOR, any mu agonist could be a suitable substitute, but the only ones approved for this purpose in the United States are methadone and LAAM (L-ALPHA ACETYLMETHADOL). These medical agents are effective when taken by mouth. Methadone can completely suppress the opioid abstinence syndrome. This capacity of one opioid to prevent the manifestations of physical dependence from another is called cross-dependence.

Outpatient detoxification using methadone typically involves using doses of 20 to 40 milligrams per day for a few days and then gradually reducing the dose over several weeks. Because so many patients return to illicit drug use as the dose of methadone approaches zero, government regulations controlling methadone permit a long period (up to 180 days) of slow dose reduction.

When detoxification takes place in a hospital or other residential setting, where the patient is presumably not as likely to be exposed to environmental cues that elicit CRAVING for opioids, dose reductions of methadone can be more rapid (e.g., over 8 to 10 days), although the intensiy of discomfort will be higher.

Other opioid agonists and partial agonists that have been used satisfactorily to facilitate detoxification include BUPRENORPHINE, (Buprenex) a partial mu agonist, and LAAM (Levomethadyl acetate). The opioid withdrawal syndrome can also be modified and reduced in severity by using agents that do not act at the mu receptors, but instead act on some of the physiological systems that exhibit hyperactivity as part of the syndrome. The use of CLONIDINE (Catapres) is an example.

The opiate antagonist NALTREXONE (Trexan) can be used to detoxify patients rapidly and to help detoxified addicts stay off opioids. Naltrexone binds more strongly than heroin to the specific brain receptors to which heroin binds. The withdrawal is usually more severe than that which comes from simply stopping the heroin, but it also has the effect of detoxifying more quickly. Thus, a combination treatment of clonidine to suppress the intensity of withdrawal symptoms and naltrexone to accelerate the pace of withdrawal has been used for rapid detoxification.

Because opioid withdrawal is time-limited and rarely life-threatening, many nonmedical treatments have also been used, including ACUPUNCTURE and herbal medicines. Another nonmedical treatment that has been used in addicts is transcutaneous electrical nerve stimulation (TENS). It is thought that both acupuncture and TENS may be helpful because they stimulate the parts of the central nervous system that release natural opioids. At present, further research is needed because opioid addicts are very suggestible and may feel better after acupuncture or TENS because of the placebo effect.

NAUSEA AND VOMITING

Nausea and vomiting are common side effects associated with the use of opioid analgesics. These effects are experienced following administration of opioids orally, by injection, or by injection into the spinal canal (epidurally)—they are worsened by movement and the resulting stimulation of the vestibular (inner ear organ responsible for balance). The site and mechanism responsible for these actions of opioids is presumed to be a special area in the brain stem or medulla, the chemoreceptive trigger zone of the area postrema.

CONSTIPATION

Constipation, an often undesirable effect of opioids, is sometimes a useful effect for which opioids can be prescribed. It is undesirable when opioids are used for the relief of pain and in opioid-dependence maintenance therapy.

The oldest of the therapeutic actions of opiates is their antidiarrheal and constipating effects. It is now known that the extrinsic innervation (nerves leading from the central nervous system to the gut) and the intrinsic innervation (nerves within the wall) of the gastrointestinal (GI) tract are complex and vary from species to species. A variety of naturally occurring neurones with diverse neurotransmitters have been identified, including neurones and their process that contain opioid peptides: the enkephalins, B-endorphin, dynorphins, and other ligands derived from pro-opiomelanocortin. Further mu and delta opioid receptors have been identified in the GI tract. The vagus nerve also has fibers that contain enkephalins, and the central nervous system has opioid mechanisms that modulate GI movement (motility).

Several influences must play a role in the constipating effects of opiate agonists—these include increased segmental activity, decreased propulsive activity, and decreased secretory activity. Naloxone, even when administered in high doses for a long period of time in antagonist therapy of opioid abusers, does not produce an overt stimulation of the GI tract resulting in diarrhea. When opioid antagonists are administered to opioid-dependent subjects, however, GI cramps and diarrhea develop as classic opioid withdrawal signs.

PRURITUS

The ability of morphine-like drugs to produce the sensation of itching (pruritus) is well known, and it is a discomforting complication when opioids are administered for therapeutic reasons. Further, many morphine-like drugs (e.g., codeine) release histamine from white blood cells that store it (mast cells and basophils). When morphine is administered intravenously, wheals (hives—raised red lumps) may appear at the site of the injection and along the course of the vein. The wheals may be associated with the sensation of itching. Occasionally, large doses of morphine may produce generalized itching. Rarely does morphine produce pulmonary edema (fluid in the air sacs of the lung), bronchoconstriction (narrowing of the air tubes in the lungs), or wheezing. With the advent of the use of intrathecal and epidural morphine (injection of morphine into spinal fluid or around the lining of the spinal canal) in pain management, the incidence of morphine-induced pruritus has become greater. Under this circumstance, the distribution of itching may be segmental (limited to the part of the spinal cord involved). Itching remains an elusive phenomenon and is harder to define and investigate than pain. It is thought that it may be mediated by a subgroup of nociceptive (pain-carrying) C fibers. Further, morphine's histamine-releasing property has been implicated in its ability to produce itching, as histamine does in allergic reactions.

CONVULSIONS

Although most opiates produce convulsions when administered in very large doses, convulsions are most frequently observed when excessively large doses of MEPERIDINE (Demerol) or d-propoxyphene (Darvon) are administered. Emergent meperidine seizures are characterized by tremors and twitching, which may evolve into tonic-clonic (epileptic) convulsions. Focal and tonic-clonic seizures have been observed in patients overdosed with d-propoxyphene. The mechanisms whereby opioid drugs produce convulsive phenomena are not well understood and may involve several mechanisms, including (1) direct and indirect dysinhibition of glycine and GABA-mediated inhibition and (2) excitatory actions that are probably mediated by yet-to-be-classified receptors. The convulsant effects of d-propoxyphene can be readily antagonized by naloxone; however, meperidine's convulsant effects may be more resistant. Meperidine probably has a convulsant effect in its own right when administered in very large doses acutely, yet convulsant phenomena seen following the administration of multiple doses of meperidine are produced by the accumulation of a metabolite, normeperidine.

DYSPHORIA, DELUSIONS, AND HALLUCINATIONS

It is rare for morphine-like analgesics to produce psychotic reactions. In patients with severe pain and discomfort and in opiate addicts, single doses of morphine-like drugs most commonly produce feelings of well-being. In normal subjects with no pain or with only modest levels of discomfort, morphine produces feelings of apathy and enervation, which are somewhat dysphoric. The drug d-propoxyphene (Darvon) has been reported to produce bizarre reactions—delusions and hallucinations—particularly when taken chronically in large doses and when used to suppress opioid abstinence. Some agonists-antagonists (e.g., pentazocine [Talwin], nalorphine, and cyclazocine) produce feelings of apathetic sedation, perceptual distortions, anxiety, delusion, and hallucinations.

STREET DRUGS

The complications described in the preceding sections are most commonly associated with pure, unadulterated opioids. When street drugs are used, which are typically diluted by the seller with quinine, lactose, or other powdered materials—and injected by the user in an unhygienic manner, in doses that vary significantly—the range of complications widens. These are described fully in the entry on neurological complications, but among the complications of heroin use reported in the medical literature are strokes, inflammation of cerebral (brain) blood vessels, toxic amblyopia, bacterial meningitis, aneurysms and brain abscesses, disorders of peripheral nerves, impairment of segments of the spinal cord, and widespread injury to muscle tissue (rhabdomyolysis)—which by releasing muscle protein can denote damage to the kidneys.

OTHER MEDICAL COMPLICATIONS

Medical complications of opioid addiction may result from unsanitary administration of the drug, from overdosing, from intoxicated behavior (e.g., unsafe sex), or from the chemical properties of opioids themselves.

Lungs.

Opioid addiction may lead to pneumonia, aspiration pneumonitis, lung abscess, or septic emboli in the lungs. It also decreases the vital capacity and diffusion capacity of lung tissue. Opioid addicts who also smoke tobacco are at increased risk of lung infections.

Liver.

Opioid addicts frequently develop viral hepatitis (types A, B, and C). In addition, addicts who are also heavy drinkers have a high incidence of cirrhosis and other disorders of liver function.

Immune System.

Hypergammaglobulinemia (an abnormally high level of gamma globulin in the blood) develops in about 90 percent of opioid addicts. As of 1999, it is unclear whether this change in the immune system is caused by infections or by daily injections of foreign substances. It diminishes in addicts on methadone maintenance. In addition to hypergammaglobulinemia, opioid addicts are at a very high risk of contracting HIV infection from shared needles.

Muscles and Bones.

Osteomyelitis (inflammation of bone and the bone marrow caused by bacterial infection) is a common complication of opioid addiction. Drug abuser's elbow is a complication in which the muscles of the lower arm are damaged by repeated needle punctures and tears.

Skin and Lymphatic System.

Opioid addicts frequently develop skin abscesses and ulcerated areas from injecting heroin under the skin ("skin popping"). Using contaminated needles may result in cellulitis, lymphangitis, lymphadenitis, and phlebitis (inflammation of a major vein).

Pregnancyand Lactation.

Infants of opioid-addicted mothers are born physically dependent on the drug, because both heroin and methadone cross the placental barrier. They may also acquire HIV infection or hepatitis from an infected mother. Pregnant addicts should be encouraged to enter a methadone maintenance program rather than attempt complete withdrawal, because withdrawal in the last trimester of pregnancy may cause early labor. Mothers on methadone maintenance can nurse infants without harm to the child, because breast milk will not contain large amounts of the methadone.

(SEE ALSO: Addiction: Concepts and Definitions)

WILLIAM R. MARTIN

REVISED BY REBECCA J. FREY AND

REBECCA MARLOW-FERGUSON