- Email: [email protected]
Low versus high doses of methadone
Sl18
S.13. Treatment options for opiate dependence
compound was shown to exhibit some weak agonism. Therefore (+)-UH-232 is either a neutral antagonist or a weak agonist in contrast to the antipsychotic drugs which are full inverse agonists at the D2 receptor. There is then the question of the physiological relevance of the observation of inverse agonism of the antipsychotic drugs. All of the antipsychotic drugs tested possess inverse agonist activity at the D2 receptor and this is seen for different chemical classes of drugs and whether the drug produces extrapyramidal side effects or not. (+)-UH-232 has been tested as an antipsychotic and was found to be devoid of clinical effect. It seems, therefore, that the property of inverse agonism may be linked to the occurrence of antipsychotic effects although it is not possible to rule out a link also with production of side effects. If we suppose that the property of inverse agonism is linked to the antipsychotic effects, what could the mechanism be? In the therapy of schizophrenia the antipsychotic drugs are used chronically and it seems that this chronic treatment is necessary to treat the positive symptoms of the disorder. The requirement for chronic treatment suggests that there is some kind of adaptive process occurring and this is most likely to be a change in the sensitivity of certain synapses in the brain. There are many studies on the chronic treatment of experimental animals with antipsychotics where an up-regulation of dopamine receptors (D2like) occurs in the brain and this requires chronic treatment with the drugs. The up-regulation of dopamine receptors, therefore, may be involved in the changes in synaptic efficacy and this leads to a reduction in the positive symptoms. This up-regulation of D2like receptors would therefore be central to the ability of the drugs to change synaptic efficacy and hence achieve an antipsychotic effect. Additionally, it has been proposed that the property of inverse agonism of a drug may lead to up-regulation of receptors. Hence for the antipsychotics their inverse agonism may be central to their therapeutic effects. Therefore the treatment of patients with the antipsychotic drugs may be leading to an up-regulation of the D2 receptors in the brain, altering the sensitivity of dopamine synapses and suppressing the psychotic symptoms experienced by the patients. These effects are dependent on the inverse agonist property of the drugs.
References [1] Coldwell MC, Boyfield I, Brown AM, Stemp G and Middlemiss DN (1999) Pharmacological characterisation of extracellular acidification rate response in human D21ong, D3 and D4.4 receptors expressed in CHO cells. Brit J Pharmacol 127:1135-1144 [2] Lahti AC, Weiler M, Carlsson A and Tamminga CA (1998) Effects of the D-3 and autoreceptor preferring dopamine antagonist (+)-UH-232 in schizophrenia. J Neural Trans 105, 719-734. [3] Strange PG (2001) Antipsychotic drugs: importance of dopamine receptors for mechanisms of therapeutic actions and side effects. Pharmacol Rev 53 119-133 [4] Strange PG (2002) Mechanisms of inverse agonism at G protein coupled receptors. Trends Pharmacol Sci 23 89-95 [5] Wilson J, Fu D, Lin H, Javitch JA and Strange PG (2001) Mechanisms of inverse agonism of antipsychotic drugs at the D2 dopamine receptor: use of a mutant D2 dopamine receptor that adopts the activated conformation. J Neurochem 77 493-504
S.13. Treatment options for opiate dependence ~ L o w
versus high doses of methadone
E. Strain. Johns Hopkins University School of Medicine, Dept. of Psych. & Behavioral Sciences, Baltimore, Maryland, U.S.A. Methadone is a mu agonist opioid used for the treatment of opioid addiction (Strain and Stitzer 1999). Methadone's pharmacological characteristics good oral bioavailability, a long duration of action, suppression of opioid withdrawal, and cross tolerance to other opioids - make it an ideal medication for the treatment of this disorder. Methadone treatment is typically composed of two ingredients - methadone medication, and non-pharmacological services (e.g., counseling, urine testing, group therapy, behavioral interventions). Methadone treatment when properly delivered is remarkable effective, and it provides an ideal setting to address other comorbid conditions commonly found in this population. Methadone has been used for the treatment of opioid dependence for over 30 years, and is the primary pharmacological treatment for opioid dependence in most countries. The appropriate methadone dose has been a recurrent issue throughout the history of this medication's use. Studies of methadone in the 1960s and 1970s used doses in excess of 100 mg/day. Clinical practice during the 1980s and 1990s generally used average doses that were <100 mg/day, especially in the USA. There are several possible reasons clinicians used these lower doses: a general philosophical shift in medicine to using the lowest effective dose of medications to minimize side effects; the perception prescribing higher methadone doses meant patients were abusing methadone; and, the belief patients receiving methadone should have their dose lowered as a punishment for continued illicit opioid use. None of these rationales are clinically appropriate. In addition to these reasons, regulatory restrictions in the USA (where the largest population of methadone maintained patients reside) discouraged the use of methadone doses >100 mg/day. Finally, it may be that the lack of well-controlled clinical trials testing doses >100 mg/day contributes to the use of lower doses of methadone. While doses of methadone <100 mg/day have been usual practice in most of the USA, this has not been the case in other parts of the world. It appears that doses >100 mg/day are more commonly used in other countries. The issue of "low" versus "high" dose methadone is complicated by the lack of well-accepted definitions of a low and high dose of methadone. Low dose methadone is unacceptable if it means the patient is being under-dosed. Controlled clinical trials with methadone have shown doses as low as 20 mg/day can maintain a small but significant proportion of outpatients in treatment. This probably reflects methadone's ability to suppress opioid withdrawal at relatively low doses. However, for the majority of patients this dose of methadone is not effective in suppressing illicit opioid use. Methadone doses between 50-100 mg/day provide increasing efficacy in suppressing illicit opioid use (Strain et al. 1999). However, a recent controlled study of heroin effects in patients maintained on 120 mg/day of methadone showed that even this dose - which some would consider a high dose - did not completely block the effects of heroin (Donny et al. 2001). Naturalistic studies of methadone dosing in clinic settings have shown patients maintained on doses of ~<100 rag/day who continue
S. 13. Treatment options for opiate dependence illicit opioid use, have decreased opioid use when their daily dose is increased to >100 mg/day (Robles et al. 2001) (Leavitt et al. 2000). In order to assist the discussion of appropriate methadone dosing, it is proposed that the following definitions be used: low dose methadone, <50 mg/day; moderate dose methadone, 50100 mg/day; and, high dose methadone, >100 rag/day. Evidence from both controlled studies and clinical experience suggests the following general conclusions regarding methadone dosing: 1. Dose should be individualized for the patient and should be in response to clinical indicators - especially withdrawal suppression (early in treatment stabilization) and attenuation of illicit opioid use (as treatment progresses). 2. Initial dose stabilization should be at least in the moderate dose range unless prior experience suggests low doses are sufficient. 3. Evidence of continued opioid use (e.g., urine samples opioid positive), and/or patient reports of craving to use opioids should be treated with an increase in the methadone dose - not a dose decrease. 4. The evaluation of continued illicit opioid use should also consider the patient's level of motivation and commitment to treatment. 5. A methadone serum level may assist in clinical management if there is concern about the efficacy of high dose methadone. It may be used to reassure the clinician when considering dose increases that are markedly high (e.g., >200 mg/day), but should be interpreted in the clinical context of the patient. 6. There is no well-accepted upper limit to methadone dosing. The clinician should carefully document reasoning when using very high doses of methadone (e.g., >300 mg/day). But, there are anecdotal reports clinicians use doses >600 mg/day. 7. The importance of the non-pharmacological aspects of methadone treatment should also be factored into dose decisions. These aspects of treatment can be very effective in addressing continued illicit opioid use. Methadone medication can be highly effective and safe when properly used for the treatment of opioid dependence. Low methadone doses should not be the initial step in treatment, but may be indicated in a small proportion of patients. For the patient motivated and interested in stopping illicit opioid use, methadone dose should be increased to maximize the opportunity to achieve abstinence and patient comfort level.
References [1] Donny EC, Stitzer ML, Bigelow GE, Walsh SL (2001) Methadone maintenance in inpatient opiate abusers suppresses withdrawal, but fails to completely block heroin effects. Drug Alcohol Depend 63: $40. [2] Leavitt SB, Shinderman M, Maxwell S, Eap CB, Paris P (2000) When "enough" is not enough: new perspectives on optimal methadone maintenance dose. Mt Sinai J Med 67:404-11. [3] Robles E, Miller FB, Gilmore-Thomas KK, McMillan DE (2001) Implementation of a clinic policy of client-regulated methadone dosing. J Subst Abuse Treat 20: 225-30; discussion 231. [4] Strain EC, Bigelow GE, Liebson IA, Stitzer ML (1999) Moderatevs high-dose methadone in the treatment of opioid dependence: a randomized trial [see comments]. JAMA 281:1000-5 [5] Strain EC, Stitzer ML (1999) Methadone Treatment for Opioid Dependence. Johns Hopkins University Press, Baltimore, MD, pp 334
•
Evidence-based treatment with buprenorphine
W. Ling. UCLA, Los Angeles, CA, U.S.A. Noting that buprenorphine possesses clinical characteristic of both methadone and naltrexone, Jasinski and colleagues (1978)
Sl19
explored its use for treatment of opiate dependence, demonstrating its ability to substitute for heroin, suppress withdrawal, and block subsequently administered heroin. Other early work (Mendelson, Mello, Bickel, Bigelow, Stitzer, Kosten and others) showed buprenorphine to be safe and efficacious in clinical settings. Subsequent controlled clinical trials have established buprenorphine's clinical efficacy and safety from a medication development perspective, making it the next evidence-based opiate pharmacotherapy to become available to clinicians. It has already been approved for use in many countries in Europe and in Australia and its approval in the United States, where most of the controlled clinical trials have been conducted, is imminent. Buprenorphine is a partial agonist at the mu receptor and a weak antagonist at the kappa receptor. It is uniquely advantageous for treatment of opiate dependence because its ceiling effect confers on it a high profile of clinical safety with a low level of physical dependence, mild withdrawal upon cessation, and low risk of lethal overdose. Its slow dissociation from the receptors provides a long duration of action, allowing for dosing from several times daily to two or three times weekly. After oral administration, buprenorphine is poorly absorbed and exhibits a large first pass effect; it is well absorbed when given sublingually, reaching 6070 percent of the plasma concentration achieved by parenteral routes. It is widely distributed throughout the body with peak plasma concentration of approximately 90 minutes and a terminal half-life of 4-5 hours. It is highly bound to plasma protein and is metabolized by N-dealkylation and conjugation. Buprenorphine metabolites are mostly excreted via the fecal route. The series of controlled clinical trials that established the safety and efficacy of buprenorphine (Ling et al, 2001) involved more than 1000 patients treated from weeks to a year and used doses ranging from 1-2 mg to 16-32 rag. Common outcome measures included illicit opiate use, retention in treatment, craving, and global rating of improvement. Overall, the studies proved that buprenorphine reduces opiate use, retains patients in treatment, produces few side effects, and is acceptable to most addicts. Dose-finding studies using the sublingual liquid indicated that the median effective dose was in the range of 12-16 mg per day. Studies using the tablet formulation, with and without naloxone, showed that while the bioavailability of the tablet may be low in single-dose administrations, it approaches that of the liquid with chronic dosing. Of the reported controlled clinical trials, two compared buprenorphine to active or inactive placebo, four were fixed dose comparisons of buprenorphine and methadone, and one used variable doses of methadone and buprenorphine. The largest of these studies, involving 736 patients in 12 sites across the U.S. and Puerto, compared four buprenorphine doses (1, 4, 8 & 16 mg), but was deemed placebo controlled since, by prior agreement with the U.S. Food and Drug Administration (FDA), 1 mg buprenorphine was considered active placebo. The only true placebo-controlled study compared, in double-blind manner, patients assigned to either placebo, 2 mg or 8 mg buprenorphine for the first two weeks of treatment, using drug use and request for dose changes as measures of outcome. To address potential diversion and intravenous abuse, buprenorphine was combined with naloxone, a pure opiate antagonist marketed for treatment of narcotic overdose (Narcan). Because buprenorphine is readily absorbed under the tongue and naloxone is not, the combination results in only buprenorphine effect when taken sublingually but if injected, the naloxone effect becomes evident and induces acute withdrawal in opiate dependent persons. Laboratory studies showed buprenorphine to become less
S.13. Treatment options for opiate dependence
compound was shown to exhibit some weak agonism. Therefore (+)-UH-232 is either a neutral antagonist or a weak agonist in contrast to the antipsychotic drugs which are full inverse agonists at the D2 receptor. There is then the question of the physiological relevance of the observation of inverse agonism of the antipsychotic drugs. All of the antipsychotic drugs tested possess inverse agonist activity at the D2 receptor and this is seen for different chemical classes of drugs and whether the drug produces extrapyramidal side effects or not. (+)-UH-232 has been tested as an antipsychotic and was found to be devoid of clinical effect. It seems, therefore, that the property of inverse agonism may be linked to the occurrence of antipsychotic effects although it is not possible to rule out a link also with production of side effects. If we suppose that the property of inverse agonism is linked to the antipsychotic effects, what could the mechanism be? In the therapy of schizophrenia the antipsychotic drugs are used chronically and it seems that this chronic treatment is necessary to treat the positive symptoms of the disorder. The requirement for chronic treatment suggests that there is some kind of adaptive process occurring and this is most likely to be a change in the sensitivity of certain synapses in the brain. There are many studies on the chronic treatment of experimental animals with antipsychotics where an up-regulation of dopamine receptors (D2like) occurs in the brain and this requires chronic treatment with the drugs. The up-regulation of dopamine receptors, therefore, may be involved in the changes in synaptic efficacy and this leads to a reduction in the positive symptoms. This up-regulation of D2like receptors would therefore be central to the ability of the drugs to change synaptic efficacy and hence achieve an antipsychotic effect. Additionally, it has been proposed that the property of inverse agonism of a drug may lead to up-regulation of receptors. Hence for the antipsychotics their inverse agonism may be central to their therapeutic effects. Therefore the treatment of patients with the antipsychotic drugs may be leading to an up-regulation of the D2 receptors in the brain, altering the sensitivity of dopamine synapses and suppressing the psychotic symptoms experienced by the patients. These effects are dependent on the inverse agonist property of the drugs.
References [1] Coldwell MC, Boyfield I, Brown AM, Stemp G and Middlemiss DN (1999) Pharmacological characterisation of extracellular acidification rate response in human D21ong, D3 and D4.4 receptors expressed in CHO cells. Brit J Pharmacol 127:1135-1144 [2] Lahti AC, Weiler M, Carlsson A and Tamminga CA (1998) Effects of the D-3 and autoreceptor preferring dopamine antagonist (+)-UH-232 in schizophrenia. J Neural Trans 105, 719-734. [3] Strange PG (2001) Antipsychotic drugs: importance of dopamine receptors for mechanisms of therapeutic actions and side effects. Pharmacol Rev 53 119-133 [4] Strange PG (2002) Mechanisms of inverse agonism at G protein coupled receptors. Trends Pharmacol Sci 23 89-95 [5] Wilson J, Fu D, Lin H, Javitch JA and Strange PG (2001) Mechanisms of inverse agonism of antipsychotic drugs at the D2 dopamine receptor: use of a mutant D2 dopamine receptor that adopts the activated conformation. J Neurochem 77 493-504
S.13. Treatment options for opiate dependence ~ L o w
versus high doses of methadone
E. Strain. Johns Hopkins University School of Medicine, Dept. of Psych. & Behavioral Sciences, Baltimore, Maryland, U.S.A. Methadone is a mu agonist opioid used for the treatment of opioid addiction (Strain and Stitzer 1999). Methadone's pharmacological characteristics good oral bioavailability, a long duration of action, suppression of opioid withdrawal, and cross tolerance to other opioids - make it an ideal medication for the treatment of this disorder. Methadone treatment is typically composed of two ingredients - methadone medication, and non-pharmacological services (e.g., counseling, urine testing, group therapy, behavioral interventions). Methadone treatment when properly delivered is remarkable effective, and it provides an ideal setting to address other comorbid conditions commonly found in this population. Methadone has been used for the treatment of opioid dependence for over 30 years, and is the primary pharmacological treatment for opioid dependence in most countries. The appropriate methadone dose has been a recurrent issue throughout the history of this medication's use. Studies of methadone in the 1960s and 1970s used doses in excess of 100 mg/day. Clinical practice during the 1980s and 1990s generally used average doses that were <100 mg/day, especially in the USA. There are several possible reasons clinicians used these lower doses: a general philosophical shift in medicine to using the lowest effective dose of medications to minimize side effects; the perception prescribing higher methadone doses meant patients were abusing methadone; and, the belief patients receiving methadone should have their dose lowered as a punishment for continued illicit opioid use. None of these rationales are clinically appropriate. In addition to these reasons, regulatory restrictions in the USA (where the largest population of methadone maintained patients reside) discouraged the use of methadone doses >100 mg/day. Finally, it may be that the lack of well-controlled clinical trials testing doses >100 mg/day contributes to the use of lower doses of methadone. While doses of methadone <100 mg/day have been usual practice in most of the USA, this has not been the case in other parts of the world. It appears that doses >100 mg/day are more commonly used in other countries. The issue of "low" versus "high" dose methadone is complicated by the lack of well-accepted definitions of a low and high dose of methadone. Low dose methadone is unacceptable if it means the patient is being under-dosed. Controlled clinical trials with methadone have shown doses as low as 20 mg/day can maintain a small but significant proportion of outpatients in treatment. This probably reflects methadone's ability to suppress opioid withdrawal at relatively low doses. However, for the majority of patients this dose of methadone is not effective in suppressing illicit opioid use. Methadone doses between 50-100 mg/day provide increasing efficacy in suppressing illicit opioid use (Strain et al. 1999). However, a recent controlled study of heroin effects in patients maintained on 120 mg/day of methadone showed that even this dose - which some would consider a high dose - did not completely block the effects of heroin (Donny et al. 2001). Naturalistic studies of methadone dosing in clinic settings have shown patients maintained on doses of ~<100 rag/day who continue
S. 13. Treatment options for opiate dependence illicit opioid use, have decreased opioid use when their daily dose is increased to >100 mg/day (Robles et al. 2001) (Leavitt et al. 2000). In order to assist the discussion of appropriate methadone dosing, it is proposed that the following definitions be used: low dose methadone, <50 mg/day; moderate dose methadone, 50100 mg/day; and, high dose methadone, >100 rag/day. Evidence from both controlled studies and clinical experience suggests the following general conclusions regarding methadone dosing: 1. Dose should be individualized for the patient and should be in response to clinical indicators - especially withdrawal suppression (early in treatment stabilization) and attenuation of illicit opioid use (as treatment progresses). 2. Initial dose stabilization should be at least in the moderate dose range unless prior experience suggests low doses are sufficient. 3. Evidence of continued opioid use (e.g., urine samples opioid positive), and/or patient reports of craving to use opioids should be treated with an increase in the methadone dose - not a dose decrease. 4. The evaluation of continued illicit opioid use should also consider the patient's level of motivation and commitment to treatment. 5. A methadone serum level may assist in clinical management if there is concern about the efficacy of high dose methadone. It may be used to reassure the clinician when considering dose increases that are markedly high (e.g., >200 mg/day), but should be interpreted in the clinical context of the patient. 6. There is no well-accepted upper limit to methadone dosing. The clinician should carefully document reasoning when using very high doses of methadone (e.g., >300 mg/day). But, there are anecdotal reports clinicians use doses >600 mg/day. 7. The importance of the non-pharmacological aspects of methadone treatment should also be factored into dose decisions. These aspects of treatment can be very effective in addressing continued illicit opioid use. Methadone medication can be highly effective and safe when properly used for the treatment of opioid dependence. Low methadone doses should not be the initial step in treatment, but may be indicated in a small proportion of patients. For the patient motivated and interested in stopping illicit opioid use, methadone dose should be increased to maximize the opportunity to achieve abstinence and patient comfort level.
References [1] Donny EC, Stitzer ML, Bigelow GE, Walsh SL (2001) Methadone maintenance in inpatient opiate abusers suppresses withdrawal, but fails to completely block heroin effects. Drug Alcohol Depend 63: $40. [2] Leavitt SB, Shinderman M, Maxwell S, Eap CB, Paris P (2000) When "enough" is not enough: new perspectives on optimal methadone maintenance dose. Mt Sinai J Med 67:404-11. [3] Robles E, Miller FB, Gilmore-Thomas KK, McMillan DE (2001) Implementation of a clinic policy of client-regulated methadone dosing. J Subst Abuse Treat 20: 225-30; discussion 231. [4] Strain EC, Bigelow GE, Liebson IA, Stitzer ML (1999) Moderatevs high-dose methadone in the treatment of opioid dependence: a randomized trial [see comments]. JAMA 281:1000-5 [5] Strain EC, Stitzer ML (1999) Methadone Treatment for Opioid Dependence. Johns Hopkins University Press, Baltimore, MD, pp 334
•
Evidence-based treatment with buprenorphine
W. Ling. UCLA, Los Angeles, CA, U.S.A. Noting that buprenorphine possesses clinical characteristic of both methadone and naltrexone, Jasinski and colleagues (1978)
Sl19
explored its use for treatment of opiate dependence, demonstrating its ability to substitute for heroin, suppress withdrawal, and block subsequently administered heroin. Other early work (Mendelson, Mello, Bickel, Bigelow, Stitzer, Kosten and others) showed buprenorphine to be safe and efficacious in clinical settings. Subsequent controlled clinical trials have established buprenorphine's clinical efficacy and safety from a medication development perspective, making it the next evidence-based opiate pharmacotherapy to become available to clinicians. It has already been approved for use in many countries in Europe and in Australia and its approval in the United States, where most of the controlled clinical trials have been conducted, is imminent. Buprenorphine is a partial agonist at the mu receptor and a weak antagonist at the kappa receptor. It is uniquely advantageous for treatment of opiate dependence because its ceiling effect confers on it a high profile of clinical safety with a low level of physical dependence, mild withdrawal upon cessation, and low risk of lethal overdose. Its slow dissociation from the receptors provides a long duration of action, allowing for dosing from several times daily to two or three times weekly. After oral administration, buprenorphine is poorly absorbed and exhibits a large first pass effect; it is well absorbed when given sublingually, reaching 6070 percent of the plasma concentration achieved by parenteral routes. It is widely distributed throughout the body with peak plasma concentration of approximately 90 minutes and a terminal half-life of 4-5 hours. It is highly bound to plasma protein and is metabolized by N-dealkylation and conjugation. Buprenorphine metabolites are mostly excreted via the fecal route. The series of controlled clinical trials that established the safety and efficacy of buprenorphine (Ling et al, 2001) involved more than 1000 patients treated from weeks to a year and used doses ranging from 1-2 mg to 16-32 rag. Common outcome measures included illicit opiate use, retention in treatment, craving, and global rating of improvement. Overall, the studies proved that buprenorphine reduces opiate use, retains patients in treatment, produces few side effects, and is acceptable to most addicts. Dose-finding studies using the sublingual liquid indicated that the median effective dose was in the range of 12-16 mg per day. Studies using the tablet formulation, with and without naloxone, showed that while the bioavailability of the tablet may be low in single-dose administrations, it approaches that of the liquid with chronic dosing. Of the reported controlled clinical trials, two compared buprenorphine to active or inactive placebo, four were fixed dose comparisons of buprenorphine and methadone, and one used variable doses of methadone and buprenorphine. The largest of these studies, involving 736 patients in 12 sites across the U.S. and Puerto, compared four buprenorphine doses (1, 4, 8 & 16 mg), but was deemed placebo controlled since, by prior agreement with the U.S. Food and Drug Administration (FDA), 1 mg buprenorphine was considered active placebo. The only true placebo-controlled study compared, in double-blind manner, patients assigned to either placebo, 2 mg or 8 mg buprenorphine for the first two weeks of treatment, using drug use and request for dose changes as measures of outcome. To address potential diversion and intravenous abuse, buprenorphine was combined with naloxone, a pure opiate antagonist marketed for treatment of narcotic overdose (Narcan). Because buprenorphine is readily absorbed under the tongue and naloxone is not, the combination results in only buprenorphine effect when taken sublingually but if injected, the naloxone effect becomes evident and induces acute withdrawal in opiate dependent persons. Laboratory studies showed buprenorphine to become less