**2. Addiction and maintenance treatment**

Opioids are commonly prescribed because of their effective analgesic, or pain-relieving, properties. Medications that fall within this class - referred to as prescription narcotics include morphine, codeine, oxycodone (e.g., OxyContin, Percodan, Percocet), and related drugs.

Morphine, for example, is often used before and after surgical procedures to alleviate severe pain. Codeine, on the other hand, is often prescribed for mild pain.

In addition to their pain-relieving properties, some of these drugs - codeine and diphenoxylate (Lomotil), for example - can be used to relieve coughs and diarrhea (National Institute on Drug Abuse, 2011).

Opioids act on the brain and body by attaching to specific proteins called opioid receptors, which are found in the brain, spinal cord, and gastrointestinal tract.

When these drugs attach to certain opioid receptors, they can block the perception of pain. Opioids can produce drowsiness, nausea, constipation, and, depending upon the amount of drug taken, depress respiration. Opioid drugs also can induce euphoria by affecting the brain regions that mediate what we perceive as pleasure. This feeling is often intensified for those who abuse opioids, when administered by routes other than those recommended. For example, OxyContin is often snorted or injected to enhance its euphoric effects, while at the same time increasing the risk of serious medical consequences, such as opioids overdose.

Many studies have shown that the properly managed, short-term medical use of opioid analgesic drugs is safe and rarely causes addiction - defined as the compulsive and uncontrollable use of drugs despite adverse consequences - or dependence, which occurs when the body adapts to the presence of a drug, and often results in withdrawal symptoms when that drug is reduced or stopped.

Withdrawal symptoms include restlessness, muscle and bone pain, insomnia, diarrhea, vomiting, cold flashes with goose bumps ("cold turkey"), and involuntary leg movements.

Taking a large single dose of an opioid could cause severe respiratory depression that can lead to death (National Institute on Drug Abuse, 2011).

Long-term use of opioids can lead to physical dependence and addiction.

Addiction continues to be referred to by terms such as drug dependence and psychological dependence (Federation of State Medical Boards of the United States, 1998).

Maintenance treatment has become a major intervention in the care and treatment of drug dependence in Europe. But still little is known about sexual behavior and sexual

A greater understanding of sexual behaviour in different maintenance treatment contexts has important consequences for the design and evaluation of substitution programs in

Sexual dysfunction has been reported as an adverse effect of opioids including methadone

In recognition of this, this chapter also aims to present specific problems and facts regarding this issue. Furthermore, the chapter presents own results regarding sexual behaviour and dysfunction prevalence within maintenance treatment. This chapter therefore provides some basic information about the main physical illnesses and impairments which can

Opioids are commonly prescribed because of their effective analgesic, or pain-relieving, properties. Medications that fall within this class - referred to as prescription narcotics include morphine, codeine, oxycodone (e.g., OxyContin, Percodan, Percocet), and related

Morphine, for example, is often used before and after surgical procedures to alleviate severe

In addition to their pain-relieving properties, some of these drugs - codeine and diphenoxylate (Lomotil), for example - can be used to relieve coughs and diarrhea (National

Opioids act on the brain and body by attaching to specific proteins called opioid receptors,

When these drugs attach to certain opioid receptors, they can block the perception of pain. Opioids can produce drowsiness, nausea, constipation, and, depending upon the amount of drug taken, depress respiration. Opioid drugs also can induce euphoria by affecting the brain regions that mediate what we perceive as pleasure. This feeling is often intensified for those who abuse opioids, when administered by routes other than those recommended. For example, OxyContin is often snorted or injected to enhance its euphoric effects, while at the same time increasing the risk of serious medical consequences, such as opioids overdose. Many studies have shown that the properly managed, short-term medical use of opioid analgesic drugs is safe and rarely causes addiction - defined as the compulsive and uncontrollable use of drugs despite adverse consequences - or dependence, which occurs when the body adapts to the presence of a drug, and often results in withdrawal symptoms

Withdrawal symptoms include restlessness, muscle and bone pain, insomnia, diarrhea, vomiting, cold flashes with goose bumps ("cold turkey"), and involuntary leg movements. Taking a large single dose of an opioid could cause severe respiratory depression that can

Addiction continues to be referred to by terms such as drug dependence and psychological

dysfunction especially under maintenance treatment.

interfere with human sexual functioning regarding addiction.

pain. Codeine, on the other hand, is often prescribed for mild pain.

which are found in the brain, spinal cord, and gastrointestinal tract.

and buprenorphine maintenance treatment.

**2. Addiction and maintenance treatment** 

Institute on Drug Abuse, 2011).

when that drug is reduced or stopped.

lead to death (National Institute on Drug Abuse, 2011).

Long-term use of opioids can lead to physical dependence and addiction.

dependence (Federation of State Medical Boards of the United States, 1998).

opioid therapy.

drugs.

The traditional distinction between addiction and habituation centers on the ability of a drug to produce tolerance and physical dependence. Tolerance is a physiological phenomenon that requires the individual to use more and more of the drug in repeated efforts to achieve the same effect.

Physical dependence manifests itself through the signs and symptoms of abstinence when the drug is withdrawn. A classic feature of physical dependence is the abstinence or withdrawal syndrome. If the addict is abruptly deprived of a drug upon which the body has physical dependence, there will ensue a set of reactions, the intensity of which will depend on the amount and length of time that the drug has been used.

Physical dependence and tolerance are normal physiological consequences of extended opioid therapy for pain and should not be considered addiction (American Academy of Pain Medicine and the American Pain Society, 1997; Commission of Public Records, 2003).

Addiction is currently also defined as a form of behavior through which an individual has impaired control with harmful consequences. Thus, individuals who recognize that their behavior is harming them or those they care about find themselves unable to stop engaging in the behavior when they try to do so (Giacomuzzi, 2008).

The severity of the medical, psychological and social harm that can be caused by addiction, together with the fact that it violates the individual's freedom of choice, means that it is appropriate to consider it to be a disorder of motivation.

A very commonly used reference text from the American Psychiatric Association – the Diagnostic and Statistical Manual of Mental Disorders – does not use the term addiction at all; rather, it uses substance dependence. And, to be more precise, the particular drug involved is specified: e.g., heroin dependence, alcohol dependence, etc.

Although other forms of treatment for opioid dependence continue to be explored, methadone maintenance treatment remains the most widely used form of treatment for people who are dependent on opioids.

Methadone maintenance treatment is a key component of a comprehensive treatment and prevention strategy to address opioid dependence and its consequences (Giacomuzzi et al., 2003; 2008; 2009).

Methadone was originally developed in Germany as a substitute analgesic for morphine. World War II brought the formula to the attention of North American researchers, who subsequently discovered that methadone could be used to treat heroin withdrawal symptoms in 1964 as a medical response to the post-World War II heroin epidemic in New York City (Giacomuzzi, 2008).

The principal effects of methadone maintenance are to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with heroin. Methadone works by alleviating the symptoms of opioid withdrawal. A stable and sufficient blood level of methadone stems the chronic craving for opioids.

Since methadone is a much longer acting drug than some other opioids, such as heroin, one oral dose daily prevents the onset of opioid withdrawal symptoms - including anxiety, restlessness, runny nose, tearing, nausea and vomiting - for 24 hours or longer. Methadone diminishes the euphoric effects of other opioids (cross tolerance), without necessarily causing euphoria, sedation or analgesia.

This means that self-administered illicit opioids will not lead to euphoria, making it less likely that clients/patients will either use illicit opioids or overdose (Giacomuzzi, 2008).

Methadone maintenance treatment has been demonstrated to be an effective treatment for opioid addiction and curbs the incidence thereof. Although methadone maintenance

Maintenance Therapy and Sexual Behavior 25

relative risk of discontinuing treatment than subjects receiving 50-80 mg/d methadone. In

These studies also found that the difference in the effectiveness of buprenorphine and methadone may be statistically significant, but the difference was small compared to the wide variance in outcomes achieved in different methadone treatment programmes

Randomized, controlled studies of up to 6 months' duration compared sublingual buprenorphine with methadone in opioid dependent patients. These generally demonstrated comparable efficacy with buprenorphine 8-12mg/d and methadone 30-

Nevertheless, it is buprenorphine that has gained more and more importance in addiction treatment because the correlation between dose and therapeutic effects is not linear, indicating a ceiling on the effects in patients due to its opioid agonistic–antagonistic

Buprenorphine is therefore a relatively safe substance, and its effectiveness in maintenance therapy has been proved in many studies. It has been used in Austria as a substitution drug

Further research is needed to determine whether buprenorphine treatment is more effective

It should be noted that, in an effort to prevent injection of the drug, the Buprenorphine/Naloxone – Sublingual Suboxone® formulation includes naloxone in addition to buprenorphine. Until now, these efforts have turned out to be less fruitful and the acceptance of this new group of preparations (Suboxone®) appears to have decreased in

However, reasons which lower the acceptance on the part of the clients yet are not fully

Nowadays, apart from methadone and sublingual buprenorphine, another substitution medication is prescribed for opioid treatment, such as long-acting morphine (retarded or

Slow-release oral morphine was established in 1998 for substitution, which gives Austria an exceptional position in opioid addiction treatment compared to other European countries

Although slow-release oral morphine is used in Austria as an alternative to methadone or buprenorphine for maintenance treatment of opioid dependence, quantitative descriptions

Slow-release oral morphine is an opioid agonist with a 12–24 hour duration of action. It is indicated for use as a maintenance treatment. The slow-release form overcomes many of the disadvantages of the short-acting nature of morphine, so theoretically it should have the same treatment effects as methadone, without some of methadone's disadvantages. Therefore, slow-release oral morphine has been proposed as an alternative maintenance pharmacotherapy to methadone or sublingual buprenorphine for treatment of opioid

There have been several studies on slow-release oral morphine for maintenance therapy Giacomuzzi, 2008). Morphine is not usually administered at our clinic to children under the

this meta-analysis, buprenorphine was more effective than 20-35 mg/d methadone.

90mg/d in promoting retention in treatment and reducing illicit opioid.

than methadone in particular settings or in particular subgroups of patients.

contrast to classical buprenorphine (Subutex®).

of patient outcomes have yet to be reported.

**2.2 Slow-release oral morphine maintenance treatment** 

understood (Giacomuzzi et al., 2011).

slow-release oral morphine).

(Giacomuzzi, 2008).

dependence.

(Giacomuzzi, 2008; 2009).

characteristics.

since 1999.

treatment has been successful, it is associated with a number of problems. Up to 50% of methadone patients withdraw from treatment in the first 6 months. Daily dosing can be a burden for treatment facilities, some of which provide doses to over 900 patients a day. Patients prefer take-home doses, but they are often associated with diversion. Therefore, nowadays methadone cannot be regarded as the golden standard for all addicted persons.

There are a number of alternatives to methadone as a maintenance agent in the management of opioid dependence.

The most promising of these involve pharmacotherapies which treat patients with a pharmaceutical grade opioid which has a longer duration of action than methadone. These include the opioid partial agonist buprenorphine and the full agonist levo-alphaacetylmethadol (LAAM) (Giacomuzzi, 2008).

#### **2.1 Buprenorphine maintenance treatment**

Buprenorphine is a potent synthetic opioid analgesic initially used for the management of acute pain. Pharmacologically, buprenorphine causes morphine-like subjective effects and produces cross-tolerance to other opioids. Unlike methadone and heroin (which are full agonists), buprenorphine is a partial agonist and exerts weaker opioid effects at opioid receptor sites.

This partial agonist action appears to make buprenorphine safer in overdose. Other benefits of buprenorphine may include an easier withdrawal phase and, because of the longer duration of action, the option of alternate day dosing (Giacomuzzi et al., 2005; 2008).

It was during the initial development of buprenorphine as an analgesic in the 1970s that its potential utility as a substitution agent in the treatment of opioid dependence was recognised. Early work using buprenorphine administered subcutaneously characterised it as an opioid with low physical dependence liability with a minimal withdrawal syndrome.

Subsequently, others provided evidence that buprenorphine does produce a mild to moderate mu-agonist withdrawal syndrome. It was thought that at doses somewhat greater than those used for analgesia, it could be used in the treatment of opioid dependence. Buprenorphine also has also some advantages over methadone. As mentioned earlier, buprenorphine has a ceiling level on agonist activity, limiting adverse reactions at very high doses. Some study results suggest that a twice-weekly dosing regimen may also be possible (Petry et al., 2001).

Evidence on the efficacy of buprenorphine has come from placebo-controlled trials, fixed dosing studies of buprenorphine versus methadone maintenance treatment and variable dosing studies of buprenorphine versus methadone maintenance treatment (Giacomuzzi, 2008). Some of the fixed dose studies showed no difference in efficacy, whereas others showed superiority for methadone and yet others showed the opposite pattern.

The investigators of these fixed dose studies frequently concluded that the doses of buprenorphine or methadone chosen were too low or that poor induction regimes led to poor retention. A series of variable (or flexible) dose studies have been conducted and show essentially equivalent results for the two drugs.

The implication of the results of a meta-analytic review conducted and reported by Mattick et al. (2004) is clear for clinical practice. The authors conclude that buprenorphine is an effective treatment for heroin use in a maintenance therapy approach.

A meta-analysis comparing buprenorphine to methadone for treatment of opioid dependence found that subjects who received 8-12 mg/d buprenorphine had 1.26 times the

treatment has been successful, it is associated with a number of problems. Up to 50% of methadone patients withdraw from treatment in the first 6 months. Daily dosing can be a burden for treatment facilities, some of which provide doses to over 900 patients a day. Patients prefer take-home doses, but they are often associated with diversion. Therefore, nowadays methadone cannot be regarded as the golden standard for all addicted persons. There are a number of alternatives to methadone as a maintenance agent in the management

The most promising of these involve pharmacotherapies which treat patients with a pharmaceutical grade opioid which has a longer duration of action than methadone. These include the opioid partial agonist buprenorphine and the full agonist levo-alpha-

Buprenorphine is a potent synthetic opioid analgesic initially used for the management of acute pain. Pharmacologically, buprenorphine causes morphine-like subjective effects and produces cross-tolerance to other opioids. Unlike methadone and heroin (which are full agonists), buprenorphine is a partial agonist and exerts weaker opioid effects at opioid

This partial agonist action appears to make buprenorphine safer in overdose. Other benefits of buprenorphine may include an easier withdrawal phase and, because of the longer

It was during the initial development of buprenorphine as an analgesic in the 1970s that its potential utility as a substitution agent in the treatment of opioid dependence was recognised. Early work using buprenorphine administered subcutaneously characterised it as an opioid with low physical dependence liability with a minimal withdrawal syndrome. Subsequently, others provided evidence that buprenorphine does produce a mild to moderate mu-agonist withdrawal syndrome. It was thought that at doses somewhat greater than those used for analgesia, it could be used in the treatment of opioid dependence. Buprenorphine also has also some advantages over methadone. As mentioned earlier, buprenorphine has a ceiling level on agonist activity, limiting adverse reactions at very high doses. Some study results suggest that a twice-weekly dosing regimen may also be possible

Evidence on the efficacy of buprenorphine has come from placebo-controlled trials, fixed dosing studies of buprenorphine versus methadone maintenance treatment and variable dosing studies of buprenorphine versus methadone maintenance treatment (Giacomuzzi, 2008). Some of the fixed dose studies showed no difference in efficacy, whereas others

The investigators of these fixed dose studies frequently concluded that the doses of buprenorphine or methadone chosen were too low or that poor induction regimes led to poor retention. A series of variable (or flexible) dose studies have been conducted and show

The implication of the results of a meta-analytic review conducted and reported by Mattick et al. (2004) is clear for clinical practice. The authors conclude that buprenorphine is an

A meta-analysis comparing buprenorphine to methadone for treatment of opioid dependence found that subjects who received 8-12 mg/d buprenorphine had 1.26 times the

showed superiority for methadone and yet others showed the opposite pattern.

effective treatment for heroin use in a maintenance therapy approach.

duration of action, the option of alternate day dosing (Giacomuzzi et al., 2005; 2008).

of opioid dependence.

receptor sites.

(Petry et al., 2001).

acetylmethadol (LAAM) (Giacomuzzi, 2008).

**2.1 Buprenorphine maintenance treatment** 

essentially equivalent results for the two drugs.

relative risk of discontinuing treatment than subjects receiving 50-80 mg/d methadone. In this meta-analysis, buprenorphine was more effective than 20-35 mg/d methadone.

These studies also found that the difference in the effectiveness of buprenorphine and methadone may be statistically significant, but the difference was small compared to the wide variance in outcomes achieved in different methadone treatment programmes (Giacomuzzi, 2008; 2009).

Randomized, controlled studies of up to 6 months' duration compared sublingual buprenorphine with methadone in opioid dependent patients. These generally demonstrated comparable efficacy with buprenorphine 8-12mg/d and methadone 30- 90mg/d in promoting retention in treatment and reducing illicit opioid.

Nevertheless, it is buprenorphine that has gained more and more importance in addiction treatment because the correlation between dose and therapeutic effects is not linear, indicating a ceiling on the effects in patients due to its opioid agonistic–antagonistic characteristics.

Buprenorphine is therefore a relatively safe substance, and its effectiveness in maintenance therapy has been proved in many studies. It has been used in Austria as a substitution drug since 1999.

Further research is needed to determine whether buprenorphine treatment is more effective than methadone in particular settings or in particular subgroups of patients.

It should be noted that, in an effort to prevent injection of the drug, the Buprenorphine/Naloxone – Sublingual Suboxone® formulation includes naloxone in addition to buprenorphine. Until now, these efforts have turned out to be less fruitful and the acceptance of this new group of preparations (Suboxone®) appears to have decreased in contrast to classical buprenorphine (Subutex®).

However, reasons which lower the acceptance on the part of the clients yet are not fully understood (Giacomuzzi et al., 2011).

#### **2.2 Slow-release oral morphine maintenance treatment**

Nowadays, apart from methadone and sublingual buprenorphine, another substitution medication is prescribed for opioid treatment, such as long-acting morphine (retarded or slow-release oral morphine).

Slow-release oral morphine was established in 1998 for substitution, which gives Austria an exceptional position in opioid addiction treatment compared to other European countries (Giacomuzzi, 2008).

Although slow-release oral morphine is used in Austria as an alternative to methadone or buprenorphine for maintenance treatment of opioid dependence, quantitative descriptions of patient outcomes have yet to be reported.

Slow-release oral morphine is an opioid agonist with a 12–24 hour duration of action. It is indicated for use as a maintenance treatment. The slow-release form overcomes many of the disadvantages of the short-acting nature of morphine, so theoretically it should have the same treatment effects as methadone, without some of methadone's disadvantages. Therefore, slow-release oral morphine has been proposed as an alternative maintenance pharmacotherapy to methadone or sublingual buprenorphine for treatment of opioid dependence.

There have been several studies on slow-release oral morphine for maintenance therapy Giacomuzzi, 2008). Morphine is not usually administered at our clinic to children under the

Maintenance Therapy and Sexual Behavior 27

subjects, however, has been shown to result in improvements in mood and libido. Additionally, when given testosterone supplementation, women with normal levels of serum testosterone have demonstrated an increased sexual response mechanism (Brown &

Studies have demonstrated higher rates of sexual dysfunction in methadone-maintained groups than in the general population. Estimates of prevalence, however, vary significantly

Additionally, the prevalence of specific types of sexual dysfunction (libido, erectile, and orgasm dysfunction) has poorly been examined in detail (Brown & Zueldorff, 2007;

In one of the first studies to examine particular types of sexual dysfunction in a methadone maintained sample, Teusch et al. (1995) found men maintained on methadone to report

Similar to earlier studies, however, the severity of dysfunction and methadone dose were

Mendelson et al conducted a prospective study of the effect of acetylmethadol administration on serum testosterone levels in 13 men with opioid dependence which yielded significant results. A statistically and biologically significant decrease in serum testosterone was found 7-9 hours after acetylmethadol administration. Testosterone levels

Mendelson also conducted some of the earliest work demonstrating a relationship between methadone dose and serum testosterone concentration. When the sample (n =38) was dichotomized into groups receiving lower dose (10-60 mg) and higher dose (80-150 mg) methadone, the men receiving higher daily doses of methadone were found to be more

As further evidence of an inverse relationship between methadone dose and serum testosterone levels in this study, reductions in methadone dose were associated with

Mendelson et al found similar results in a sample of 10 men administered heroin in a controlled setting for 7 days and then detoxified using methadone at a starting dose of 35 mg. Again, abnormally low serum testosterone levels found during and after the period of heroin administration were found to recover to baseline after methadone detoxification.

Erectile dysfunction (ED) more commonly has an organic or iatrogenic etiology. A variety of systemic illnesses are associated with ED. These include chronic liver disease, renal failure, arteriosclerotic cardiovascular disease, diabetes mellitus, chronic obstructive pulmonary disease, and malignancy. Spinal trauma and genitourinary surgery are of potential etiologic

Though rarer, congenital and other anatomic genitourinary anomalies (e.g. Peyronie's Disease, phimosis, post-traumatic aneurysm) should also be considered (Brown &

Medications commonly associated with ED include antihypertensives, psychotropic agents,

Smoking, for example, is strongly associated with ED. The relative risk for ED increases by

reduced libido and orgasm dysfunction more frequently than controls.

attained normal levels 48 hours after drug administration.

likely to have abnormally low serum testosterone.

recovery of testosterone levels.

**3.2 Erectile dysfunctions** 

importance in ED, as well.

and medications with anticholinergic effects.

1.31 for every 10 pack-years of smoking.

Zueldorff, 2007).

Zueldorff, 2007).

between 30-100%.

Giacomuzzi, 2009).

unrelated.

age of 18 years, in respiratory depressions and in the presence of acute alcoholism (Giacomuzzi, 2008). Further research is needed to determine whether slow-release oral morphine treatment is more effective than methadone or buprenorphine in particular settings or in particular subgroups of patients.
