Opioid drug: Abuse and Dependence
Mark A. Schuckit, David S. Segal
Harrison's Principles of Internal Medicine 14th Ed., 1998, Chapter 387.
The principal effects of the opioids (opiate-like drugs) are a significant damping of pain perception along with modest levels of sedation and euphoria. Drugs in this category range from heroin, morphine, and codeine to many nonsteroidal prescription analgesics and many antitussive agents. Thus, the following comments have wide application in medicine and go far beyond the classical opiate-dependent person on the street.
Tolerance to any one opioid is likely to generalize to the others (i.e., cross-tolerance is likely), and all share a similar pattern of drug-related problems. Each of these substances is capable of producing dependence as defined in the Fourth Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-IV), including evidence of physical addiction (and thus they all have some legal restrictions). The abstinence syndrome from any of the substances can be treated with administration of any of the others.
The prototypic opiates, morphine and codeine (3-methoxymorphine), are taken directly from the milky juice of the poppy Papaver somniferum. The semisynthetic drugs produced from the morphine or thebane molecules include hydromorphone, diacetylmorphine (heroin), and oxycodone. The purely synthetic opioids, sharing many of the basic properties of opium and morphine, include meperidine, propoxyphene, diphenoxylate, fentanyl, buprenorphine, methadone, and pentazocine. Despite claims to the contrary, all these substances (including almost all prescription analgesics) are capable of producing euphoria as well as psychological and physical dependence when taken in high enough doses over prolonged periods.
The opioids produce their effects by binding to different types of opioid receptors throughout the body, including the central nervous system. Endogenous opioid peptides (i.e., enkephalins, endorphins, dynorphin, and others) have been identified that appear to be natural ligands for opioid receptors. These peptides have a distinct distribution in the central nervous system (CNS). Recent evidence suggests that the receptors with which opioid peptides interact may be differentially engaged in production of the various opiate effects, such as analgesia, respiratory depression, constipation, and euphoria, but the data are not definitive. Substances capable of antagonizing one or more of these actions include nalorphine, levallorphan, cyclazocine, butorphanol, buprenorphine, and pentazocine, each of which has mixed agonist and antagonist properties, as well as naloxone and naltrexone, which are pure opiate antagonists. All antagonist drugs (including those with mixed agonist properties), if administered to a patient addicted to other narcotics, can precipitate opiate withdrawal symptoms. The availability of relatively specific antagonists has helped identify different receptor subtypes, including the mu1 and mu2 subtypes, which are thought to affect some of the more classical opioid actions such as pain control, constipation, and respiration; kappa receptors, with possible similar functions along with sedation and effects on hormones; and delta receptors, thought to relate mostly to analgesia.
Opiate tolerance, dependence, and withdrawal are considered to be related phenomena and may share some common underlying mechanisms. Perhaps reflecting the actions of different classes of receptors, tolerance to various opiate actions may develop at different rates, and these same mechanisms may contribute to the diverse signs and symptoms characteristic of withdrawal. Biochemical systems that might contribute to the development of tolerance and dependence include alterations in neurotransmitters, including acetylcholine, serotonin, gamma-aminobutyric acid (GABA), and the catecholamines norepinephrine and dopamine. Behavioral conditioning also plays a role in maintaining dependence in at least some individuals.
All the opioid drugs are absorbed from the gastrointestinal system, the lungs, and/or the muscles. The most rapid and pronounced effects occur following intravenous administration, with only slightly less efficient absorption after smoking or inhaling the vapor ("chasing the dragon"), and the least intense actions are seen after absorption from the digestive tract. Most of the metabolism of opiates occurs in the liver, primarily through conjugation with glucuronic acid, and only small amounts are excreted directly in the urine or feces. The plasma half-lives of these drugs range from 2.5 to 3 h for morphine to more than 22 h for methadone and even longer for levomethadyl acetate (LAAM).
Street heroin typically contains only 5 to 10 percent of the opiate. The remainder consists of materials such as lactose and fruit sugars, quinine, powdered milk, phenacetin, caffeine, antipyrine, and strychnine, which are used to "cut" the drug and increase the profit margin. Any marked, unexpected increase in the purity of street drugs is likely to cause unintentional lethal overdoses in users expecting less effect from a "hit."
With the exception of overdose conditions and changes associated with physical addiction, most opiate actions are relatively benign and rapidly reversible. A major danger, however, comes through the use of contaminated needles by intravenous users. This practice is responsible for increased risks for hepatitis B and C, bacterial endocarditis, and infection with the human immunodeficiency virus (HIV), a major cause of mortality in injection drug users and their sexual partners.
Acute changes in the gastrointestinal (GI) system are the result of decreased GI motility with resulting constipation and anorexia. Chronic GI problems in opiate-dependent people typically occur as a consequence of hepatitis in injection drug users.
The direct effects on opiate receptors in the CNS can result in intoxication-induced nausea and vomiting (medulla), decreased pain perception (spinal cord, thalamus, and periaqueductal gray region), euphoria (limbic system), and sedation (reticular activating system and striatum). The adulterants added to street drugs may contribute to some of the more permanent nervous system damage, including peripheral neuropathy, amblyopia, myelopathy, and leukoencephalopathy. Whether from the opiate, adulterants, or the consequences of dirty needles, at least one recent study revealed CNS defects in both computed tomographic and cognition evaluations of opiate-dependent people. Acute opiate administration results in decreases in luteinizing hormone (LH), with a subsequent decrease in testosterone, which might contribute to the decreased sex drive reported by most opiate-dependent people. Other hormonal changes include a decrease in the release of thyrotropin as well as increases in prolactin and possibly in growth hormone.
Acute changes in the respiratory system include respiratory depression, which results from a decreased response of the brainstem to carbon dioxide tension, a component of the drug overdose syndrome described below. At even low drug doses, this effect can be clinically significant in individuals with compromised lung activity. Cardiovascular changes tend to be relatively mild, with no direct opiate effect on heart rhythm or myocardial contractility, but there is a potential problem from orthostatic hypotension, probably secondary to dilation of peripheral vessels. Bacterial infections of both the lungs and heart valves can occur from contaminated needles; the latter can result in emboli and thus an increased risk for stroke.
High doses of opiates taken intentionally (in a suicide attempt) or by a user who has misjudged the potency of the substance can result in a toxic reaction or overdose syndrome with a potentially lethal consequence. While toxic reactions are seen with all opiates, the more potent drugs such as fentanyl (80 to 100 times more powerful than morphine) are especially dangerous. The typical syndrome, which occurs immediately with intravenous overdose, includes shallow respirations at a rate of two to four per minute, pupillary miosis (with mydriasis once brain anoxia develops), bradycardia, a decrease in body temperature, and a general absence of responsiveness to external stimulation. If this medical emergency is not treated rapidly, symptoms can progress to cyanosis, and death can ensue from respiratory depression and cardiorespiratory arrest. Postmortem examination reveals few specific changes except for diffuse cerebral edema. An "allergic-like" reaction to intravenous heroin, apparently at least in part related to adulterants, also can occur and is characterized by decreased alertness, a frothy pulmonary edema, and an elevation in the blood eosinophil count.
The first step in treating any overdose is to support the vital signs through a respirator and other emergency procedures. The preferred, more definitive treatment for the typical opiate overdose is the intravenous or intramuscular administration of the narcotic antagonist naloxone in an initial dose of 0.2 mg (0.5 mL of the 10 mL vial) or more; this dose can be repeated in 3 to 10 min if no response occurs. It is important to titrate the dose relative to the patient's symptoms. Because the effects of this drug diminish within 2 to 3 h, the individual must be monitored for at least 24 h after a heroin overdose and 72 h after an overdose of a longer-acting drug such as methadone. If there is little response to naloxone alone, the possibility of a concomitant overdose with a benzodiazepine should be considered and a challenge with intravenous flumazenil, 0.2 to 0.5 mg/min up to a maximum of 3 mg, might be used. Patients who are physically addicted to an opioid are likely to experience a precipitous onset of an abstinence syndrome within 2 to 8 h after administration of the opioid antagonist, but aggressive treatment of this syndrome is not appropriate until all vital signs are relatively stable.
As with any drug overdose, treatment of either the typical or the "allergic" type of opiate toxic reaction often requires continued support of vital signs until the body detoxifies the substance. Patients may require a respirator (especially one using oxygen and positive-pressure breathing for the "allergic" type of overdose), intravenous fluids perhaps accompanied by pressor agents, to support blood pressure, and gastric lavage to remove any remaining drug, with care taken to use a cuffed endotracheal tube to prevent aspiration if the patient is not alert. It is important to evaluate and treat any possible anaphylactic reactions. Cardiac arrhythmias and/or convulsions, especially likely to be seen with codeine, propoxyphene, or meperidine, also need to be treated.
Repeated use of opiates to the point of developing multiple problems is a good indicator of the likelihood of future problems with the drug. The approach uses the same DSM-IV criteria for dependence as discussed for alcohol. Here, the patient develops repeated difficulties in any three of the criterion areas in any given year, showing a mixture of tolerance, withdrawal, use of greater amounts of opiates than intended, use despite consequences, and so on. Patients who do not have dependence but demonstrate repeated difficulties with the law, impaired ability to meet obligations, use in hazardous situations, or continued use despite problems can be labeled as having abuse.
Dependence on or abuse of opiates can be seen in at least three types of patients. First, evidence suggests that a minority of people with chronic pain syndromes (e.g., back, joint, and muscle disorders) misuse their prescribed drugs at various times. Of course, these comments deal with non-life-threatening chronic pain, not terminal illness, for which high doses of opiates can be important. If physical dependence is established, abstinence syndromes can then intensify the pain, promoting continued drug intake. A few precautions can help the physician to avoid contributing to physical dependence in chronic pain patients, particularly those who have demonstrated a history of misusing opioids. (1) The goal is to minimize the debilitating effects of pain with the understanding that discomfort may not be completely eliminated. (2) All possible efforts must be made to get the patient actively involved in and committed to improvement. (3) Analgesic medication should be only one component of treatment and limited to the oral administration of the least potent analgesic that is able to "take the edge off" the pain (e.g., ibuprofen or, if needed, propoxyphene). All such drugs should be coordinated through one physician. (4) Behavior modification techniques, such as muscle relaxation and meditation, and carefully selected exercises should be used as appropriate to help increase function and decrease pain. (5) Finally, nonmedicinal approaches, including electrical transcutaneous neurostimulation for muscle and joint disease, can be applied.
The second group at high risk are physicians, nurses, and pharmacists, primarily because of their easy access to substances of abuse. Physicians may begin to use opiates to help them sleep or to reduce stress or physical aches and pains. These groups appear to be at especially high risk for developing dependence on the highly potent drugs such as fentanyl. Because of the growing awareness of these problems, impaired physician programs have been established in many hospitals and by most state medical societies. These groups attempt to identify and aid substance-impaired physicians, giving them peer support and education so as to help them achieve abstinence before problems escalate to the point of licensure revocation. In general, doctors are advised never to prescribe opiates for themselves or for members of their family--physicians deserve the same level of care and protection from future problems as their patients.
The third and most obvious group are those who buy their drugs on the street to get high. While some of these men and women have prior histories of severe antisocial problems, most have a relatively high level of premorbid functioning. The typical person begins using opiates occasionally, often after experimenting with tobacco, then alcohol, then marijuana, and then brain depressants or stimulants. Occasional opiate use, or "chipping," might continue for some time, and some individuals never escalate their intake to the point of developing dependence. Another pattern of temporary or intermittent abuse is represented by the experiences of Vietnam soldiers, most of whom had little or no prior experience with opiates and who found themselves in a situation of high stress and readily available drugs. Under these circumstances, as many as one-half tried opiates and, although many became physically addicted, those who had not misused drugs before Vietnam tended to return to drug-free status when back in their home communities.
Of course, opiate-dependent individuals are likely to continue to have experience with many other drugs. At least two of these often remain as problems during the course of opiate dependence. First, alcohol intake is classically used to moderate withdrawal problems, to enhance the opiate high, and as a substitute when the preferred drug is not readily available, including during methadone and other treatments. This pattern of problematic drinking, often meeting criteria for alcohol dependence, is seen in the course of opiate dependence in perhaps 50 percent of opiate-dependent persons. The second drug, cocaine, appears to be taken for many of the same reasons as alcohol and is often administered intravenously with the opiate in a mixture known as a "speedball." Dependence on these as well as other drugs must be addressed during opiate detoxification and rehabilitation.
Once persistent opiate use is established, the outcome is often extremely serious. At least 25 percent of such opiate abusers are likely to die within 10 to 20 years of active abuse, with death resulting from suicide, homicide, accidents, and infectious diseases such as tuberculosis, serum hepatitis, or AIDS. The mortality rate has escalated in recent years in response to the epidemic of AIDS among injection drug users, with an estimated 60 percent of these men and women carrying HIV. As many as 50 percent of male and 25 percent of female opiate-dependent persons turn to alcohol when their primary drug is not available, and many meet the criteria for secondary alcohol dependence. The prevalence of alcohol misuse is higher in drug treatment dropouts than in those who stay with therapy, and also in individuals who had alcohol problems before they developed opiate-related difficulties.
The key to diagnosis is to discard the erroneous stereotype that opiate-dependent men and women are always street people. Abuse or dependence is possible in any patient who demonstrates symptoms of what might be opiate withdrawal; anyone who has a chronic pain syndrome; physicians, nurses, and pharmacists or others with easy access to opiates; and all patients who repeatedly seek out prescription analgesics. The diagnosis is established by reviewing areas of life problems where opiates might be involved, beginning with the DSM-IV items for abuse and dependence.
Identification Of The Patient, And Intervention
The first step in treatment is identification of the opiate-dependent person--an especially difficult step with middle-class medical patients or physicians with an iatrogenic addiction. Therefore, it is important to take the time with every patient, especially those with complaints of pain, to gather a clinical history that includes the patterns of opiate use and the list of doctors and clinics from which they have received prescriptions. If the chronic use of opiates is suspected, gathering further data from an additional informant such as a spouse can be essential. Another indicator of an enhanced risk for opiate dependence is a history of pervasive antisocial problems beginning in the preteen years. Blood and urine screens can be used to identify opiates in patients in whom misuse is suspected, and clinicians should search for physical stigmata of misuse (e.g., needle marks).
After identifying opiate dependence, the next step is intervention. The need for active treatment of the abstinence syndrome can be presented, and the availability of help in establishing a drug-free life-style can be emphasized. The final decision, of course, rests with the patient.
The Symptoms Of Withdrawal
The withdrawal symptoms tend to be opposite to the acute effects of the drug and include nausea and diarrhea, coughing, lacrimation, mydriasis, rhinorrhea, profuse sweating, twitching muscles, and piloerection, or "goose bumps"; mild elevations in body temperature, respiratory rate, and blood pressure are also observed. In addition, sensations of diffuse body pain, insomnia, and yawning occur, along with intense drug craving. Drugs with a short half-life, such as morphine or heroin, cause symptoms typically within 8 to 16 h of the last dose (thus, many dependent individuals awake in mild withdrawal every morning); symptom intensity peaks within 36 to 72 h after discontinuation of the drug, and the acute syndrome disappears within 5 to 8 days. However, a protracted abstinence phase of mild symptoms (e.g., slight changes in pupillary size, autonomic dysfunction, changes in sleep pattern) may persist for 6 or more months. These lingering symptoms, which can be relieved by administering an opiate, probably contribute to relapse.
Treatment Of The Withdrawal Syndrome
Patients must receive a thorough physical examination, which includes an assessment of liver and neurologic function as well as identification of local and systemic infections, especially abscesses. Proper nutrition and rest must be initiated as soon as possible.
Effective treatment of withdrawal, however, also requires readministration of sufficient opiate medication on day 1 to decrease symptoms, followed by a more gradual withdrawal of the drug, usually over 5 to 10 days. Any opiate will work (they all have some level of cross-tolerance), but for ease of administration, many physicians prefer to use a long-acting drug such as methadone. In estimating the first day's dose from the patient's history, 1 mg of methadone is approximately equivalent to 3 mg of morphine, 1 mg of heroin, or 20 mg of meperidine. Most patients require between 10 and 25 mg of methadone orally given twice on day 1, with higher doses given if prominent symptoms of withdrawal are not dampened. After several days of a stabilized drug dose, the opiate is then decreased by 10 to 20 percent of the original day's dose each day.
Most states have restrictions on the prescription of opiates to dependent persons, and, in the absence of special permits, detoxification with opiates is often proscribed or limited to 1 month or less. Thus, pharmacologic treatments are often limited to symptomatic medication of diarrhea with kaopectate or a similar nonopiate, of "sniffles" with decongestants, and pain with nonopiate analgesics (e.g., ibuprofen). Another relatively successful nonopiate approach to the treatment of withdrawal is the use of the alpha2-adrenergic agonist clonidine, used in part to decrease sympathetic nervous system overactivity. Given at doses of approximately 5 microgram/kg (up to 0.3 mg given two to four times a day), clonidine decreases autonomic nervous system dysfunction in most patients undergoing opiate withdrawal. Opiates are more effective in relieving discomfort and pain, however, and clonidine is often not well tolerated because it produces high levels of sedation and orthostatic hypotension. Therefore, under most circumstances, opiates are the treatment of choice.
A special case of opiate withdrawal is seen in the newborn passively addicted by the mother's drug misuse during pregnancy. Some level of addiction develops in 50 to 90 percent of children of heroin-dependent mothers. As few as 25 percent of infants of methadone maintenance-addicted mothers show clinically relevant withdrawal symptoms, probably because of the longer half-life of this drug. The syndrome consists of irritability, crying, a tremor (in 80 percent), increased reflexes, increased respiratory rate, diarrhea, hyperactivity (in 60 percent), vomiting (40 percent), and sneezing/yawning/hiccuping (in 30 percent). The child usually has a low birth weight but may be otherwise unremarkable until the second day, when symptoms are likely to begin.
The treatment follows the same general steps used in the treatment of the physically addicted adult. The child must be carefully evaluated to rule out medical problems such as hypoglycemia, hypocalcemia, infections, and trauma; general support in a warm, quiet environment and regulation of electrolytes and glucose are also required. The infant with moderate to severe symptoms can be treated with any of the following: paregoric (0.2 mL orally every 3 to 4 h), methadone (0.1 to 0.5 mg/kg per day), phenobarbital (8 mg/kg per day), or diazepam (1 to 2 mg/kg every 8 h). Medication should be given in decreasing levels for 10 to 20 days. It is also possible to help treat the addicted infants of mothers on methadone maintenance by having the mother breast feed the infant while continuing to take methadone.
Rehabilitation Of Opiate-Dependent Persons
Despite some differences in demographics, the same general rules for rehabilitation apply to opiate-dependent persons as to alcoholics. The basic strategy includes beginning detoxification and general family support, and the process can benefit from the use of readings or referral to self-help groups. It is also important to establish realistic patient goals and a program of counseling and education to increase motivation toward abstinence. A long-term commitment to rebuilding a life-style without the substance is essential for preventing recidivism.
Most rehabilitation approaches have common elements, regardless of the drug involved. As described in several recent texts, patients are educated about their responsibility for improving their lives, and motivation for abstinence is increased by providing information about the medical and psychological problems that can be expected if addiction continues. Patients and families are helped to establish an opiate-free life-style by being educated about dealing with chronic pain and developing realistic vocational planning (e.g., for pharmacists, physicians, and nurses). The dependent person also should be encouraged to establish a drug-free peer group and to participate in self-help groups such as Narcotics Anonymous. Much of this advice and counseling can be given by the physician, but many clinicians refer patients to more formal drug programs, including methadone maintenance clinics, programs using narcotic antagonists, and therapeutic communities. Long-term follow-up of treated patients shows that approximately one-third of participants are completely drug free in the year before the follow-up interview and that a total of 60 percent are off opiates, although some are abusing other substances. Individuals who stay in methadone maintenance or in therapeutic communities show significant decreases in police and social problems and increases in job functioning. In general, the best prognosis is for those who are employed, who have higher levels of school completion, and who remain in treatment for at least 2 months. Dependence among health care deliverers, such as physicians, is treated with similar approaches. In addition, a closely supervised "diversion" procedure is usually instituted and carried out for 1 to 2 years or more.
METHADONE MAINTENANCE
Maintenance programs with methadone and the even longer-acting agent LAAM should only be used along with education and counseling. It is important to note that drug maintenance is not aimed at "curing" opiate addiction; rather, it provides a substitute drug that is legally accessible, safer, can be taken orally, and has a long half-life so that it can be taken once a day. The goal is to help persons who have repeatedly failed in drug-free programs to improve functioning within the family and job, to decrease legal problems, and to improve health.
Methadone is a long-acting opiate that possesses almost all the physiologic properties of heroin. The recipient, who has been carefully screened to rule out prior psychiatric disorders, may be maintained on a relatively low dose (e.g., 30 to 40 mg/d); a better approach is to use a higher dose (100 to 120 mg/d), which may be more effective in blocking heroin-induced euphoria. There is some evidence that the higher methadone doses result in greater retention in treatment and consequently in lower levels of arrest and readdiction to street drugs. Three-quarters or more of patients, especially those receiving the higher doses, are likely to remain heroin-free for 6 months or longer. Methadone is administered in an oral liquid given once a day at the program center, with weekend portions taken by the patient at home. The longer-acting analogues, such as LAAM, can be given two or three times a week, with the dose of LAAM increased to as high as 80 mg three times a week if needed. After a period of maintenance (usually 6 months to 1 year or longer), the clinician should work closely with the patient to regulate the rate of drug decrease (by about 5 percent per week).
In the past, the British have used heroin maintenance with similar goals and following similar guidelines as those used for methadone. There is no evidence that heroin maintenance has any advantages over methadone maintenance, but the heroin approach does add the risk that the drug will be sold on the streets. These factors have contributed to the virtual abandonment of the heroin maintenance approach. Treatment with mixed agonists-antagonists such as buprenorphine has been proposed, especially to help the individual who is also using cocaine. However, at present these must be considered experimental.
OPIATE ANTAGONISTS
The opiate antagonists (e.g., naloxone) compete with heroin and other opiates for opioid receptors, reducing the effects of the opiate agonists. Administered over long periods with the intention of blocking the "high" produced if the patient takes opiates, these drugs can be useful as part of an overall treatment approach that includes counseling and support. The most widely used antagonist in rehabilitation is naltrexone, which is effective for about 24 h and has few side effects. A dose of 50 mg of naltrexone per day will block 15 mg of heroin for 24 h, and higher doses (125 to 150 mg) are capable of blocking the effects of 25 mg of intravenous heroin for up to 3 days. Naltrexone is free of agonist properties and produces no known withdrawal symptoms when stopped, and its side effects tend to be mild. Patients should be free of opiates for a minimum of 5 days before beginning treatment with this medication, to avoid precipitating a withdrawal syndrome. In addition, they must be given a thorough physical examination and should be challenged with 0.4 or 0.8 mg of the shorter-acting agent naloxone to be certain they are able to tolerate the long-acting antagonist. Following this procedure, a test dose of 10 mg of naltrexone can be given, with the expectation that any withdrawal symptoms will be seen in 0.5 to 2 h. Several variations of this approach can be used with methadone maintenance, including a fairly rapid, medically supervised scheme. Over the next 10 days, the daily dose should be increased to about 100 mg on Mondays and Wednesdays and 150 mg on Fridays. Unfortunately, despite the apparent advantages of this treatment approach, patients demonstrate great resistance to continuing care. In one study, only about 60 percent of the patients completed 6 days of naltrexone induction, and only 10 percent remained in the program at the end of 6 months.
DRUG-FREE PROGRAMS
Most existing halfway houses and recovery centers for opiate-dependent persons use some variant of the therapeutic community approach. This is an exception to the general preference for short-term inpatient rehabilitation, since care lasts up to a year while the person is taken out of the street culture and given a new life within the group. In this structure, members, including leaders who are themselves in the process of recovery, help participants gain insights into more successful life-styles for coping with problems.
As is true for treatments of all substance-use disorders, it is likely that counseling, behavioral treatments, and relatively simple approaches to psychotherapy add significantly to a positive outcome. Most approaches focus on teaching participants to handle stress better, enhancing their understanding of personality attributes, teaching better cognitive styles, and, through the process of relapse prevention, addressing issues that might contribute to increased craving, easy access to drugs, or periods of decreased motivation. A combination of these therapies with the approaches described above appears to give the best results.
Finally, it is important to briefly discuss prevention. Except for the terminally ill, physicians need to carefully monitor opiate drug use in their patients, keeping the doses as low as is practical and administering them over as short a period as the level of pain would warrant in the average person. Physicians must also be vigilant regarding their own risk for opiate abuse and dependence, never prescribing these drugs for themselves. For the nonmedical intravenous drug-dependent person, all possible efforts must be made to prevent AIDS, hepatitis, bacterial endocarditis, and other consequences of contaminated needles through methadone maintenance and by considering needle-exchange programs.
© 1999 Last updated on March, the 14th, 1999.
En son 14, Mart, 2000'de yenilendi
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