International Journal of the Addictions
ISSN: 0020-773X (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/isum19
Serum Methadone as an Aid in Managing Methadone Maintenance Patients Ralph G. Walton, Thomas L. Thornton & Gerald F. Wahl To cite this article: Ralph G. Walton, Thomas L. Thornton & Gerald F. Wahl (1978) Serum Methadone as an Aid in Managing Methadone Maintenance Patients, International Journal of the Addictions, 13:5, 689-694, DOI: 10.3109/10826087809039295 To link to this article: http://dx.doi.org/10.3109/10826087809039295
Published online: 03 Jul 2009.
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Date: 20 April 2016, At: 00:07
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The International Journal of the Addictions, 13(5), 689-694, 1978
Serum Methadone as an Aid in Managing Methadone Maintenance Patients Ralph G. Walton, M.D. Thomas L. Thornton, M.D. Gerald F. Wahl, M. Div. Jamestown, New York 14701
Abstract
Serial serum methadone levels were obtained in two patients who were experiencing significant difficulties (including subjective and objective evidence of the opiate withdrawal syndrome) while on methadone maintenance. A precipitous drop in blood levels of methadone was recorded 2 to 6 hours after ingestion. It was during this same time period that withdrawal symptoms were most severe. When methadone was administered on a divided dosage regimen, there was a dramatic clinical improvement in both patients and a marked flattening of the curve of serum methadone levels. This pilot. study suggests that the current practice of administering methadone as a single daily dose to all patients needs reconsideration; serial serum methadone levels may be helpful in determining which patients do better on a divided dosage regimen. 689 Copyright @ 1978 by Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher.
Downloaded by [University of California, San Diego] at 00:07 20 April 2016
690
WALTON. THORNTON, AND W A H L
The current practice of administering methadone as a single daily dose to patients on methadone maintenance is based upon the premise that the drug has a consistently long duration of action (at least 24 hours) (Goldstein, 1972). It is essentially accepted that the high-low-high-low fluctuations experienced by the addict on heroin d o not occur with methadone addiction (Dole et al., 1966). There are, however, relatively little data to support this belief. In our survey of the literature we found only two studies looking directly at the time course of methadone in the plasma of patients on maintenance. The work on Inturrisi and Verebely (1972) was based on five patients; that of Kreek (1973) on nine. Although the smooth curves which one can plot utilizing the data presented in these studies (Fig. 1 ) may well be correct for the majority of methadone maintenance patients, the small number of patients studied and clinical experience suggest that there may be significant individual variation in the time course of methadone metabolism. Because of the important treatment implications, this pilot investigation was conducted to determine if such v a ria t ion s ex ist .
METHODS Serial serum methadone levels of two individuals on methadone maintenance were studied. These subjects were selected from a group of81 such patients currently involved with the University of Rochester Drug Treatment Program because their histories suggested an unusual pattern of- response to opiates. R.P. is a 24-year-old White married male, and father of one son. He first became involved with drugs in 1968 when he began using psychedelics and marijuana. In 1970 he began using heroin by “snorting” initially, then “mainlining” after several months. He quickly developed a habit of 18 to 30 “bags” per day at a time when a typical bag often contained from 5 to 10 mg of heroin. I n presenting his history he repeatedly made the point that both he and his girlfriend (K.P., considered below) always required more heroin than their friends, and at any party were always the last ones to “nod off.” I n 1971 he began the first of multiple unsuccessful attempts at ambulatory detoxification with methadone. He allegedly combined his methadone with both heroin and barbiturates in an attempt to relieve what he described as “severe withdrawal symptoms.” Of note in his medical history is a splenectomy at age 4 for congenital
SERUM METHADONE
69 1
spherocytosis, and asthma since childhood, currently treated with Tedral. He has a twin sister who has no known history of drug abuse.
Downloaded by [University of California, San Diego] at 00:07 20 April 2016
K. P K.P. is a 25-year-old White female, mother of one son, and married to R.P. (described above). She first became involved with drugs as a 10th grade student when she began using amphetamines, psychedelics, and marijuana. At age 20 she began “shooting” methadone and cocaine, and then heroin. She claimed to always use more heroin than her addicted friends, and in fact became involved with R.P. because they shared the problem of needing more opiates than their peers, and always were the last ones to “nod off in a shooting gallery.” She is one of three siblings, and the only member of her family known to have a history of opiate addiction. During the first several months that they were on methadone maintenance, both R.P. and K.P. persistently complained that the drug “was not holding” them, despite eventually attaining a dose level of 100 mg/day. Aside from their subjective feeling of discomfort, each demonstrated clinical evidence of the opiate withdrawal syndrome within 4 to 6 hours after the ingestion of methadone. They exhibited diaphoresis, lacrimation, rhinorrhea, piloerection, skin pallor, and tachycardia. These signs and symptoms would appear very rapidly and increase in severity over the ensuing 18 hours before they were allowed their next daily dose. Each considered dropping out of the program because of the intense physical discomfort. When it became clear that both patients were about to return to the use of street heroin in an attempt to alleviate withdrawal symptoms, we obtained serial blood samples over an 8-hour period. The serum was analyzed by gas-liquid chromatography for methadone and the major methadone metabolite, dl-2-ethyl- 1,5-dimethyI-3,3-diphenyl1-pyrolidine. Blood was drawn at the time of ingestion of the morning dose of 100 mg of methadone and again at 1, 2, 4, 6, and 8 hours. Clinical observations of the patients’ status were recorded over this period. Serial blood levels were also obtained for each patient after “stabilization” was ultimately achieved (see below).
RESULTS Within the first 2 hours after ingesting 100 mg of methadone there was a rapid rise in the serum levels of methadone and its major metabolite.
Downloaded by [University of California, San Diego] at 00:07 20 April 2016
692
WALTON, THORNTON. AND W A H L
During the next 4 hours a precipitous fall in methadone levels was recorded for both subjects. The time course of these changes is presented graphically in Fig. 1. These data correlated well with what was observed clinically. The rapid fall in the blood level of methadone came at approximately the same time as the subjective and objective evidence of opiate withdrawal. On the basis of both the clinical and laboratory data, a decision was made to administer methadone on a divided dosage regimen to R.P. and K.P. (after obtaining the necessary approval from the appropriate state and federal agencies). The hope was that “evening out’’ the fluctuating blood levels would be reflected clinically by a cessation of withdrawal symptoms. Complex empirically based changes were made in both total daily dosage and the timing of methadone administration. The end point was determined by the patients’ subjective reports of comfort and stabilization. This occurred at a total daily dose of 180 mg, divided into three doses of 80,60, and 40 mg for K.P., and 260 mg, divided into three doses of 80,40, and 20 mg and eight separate 15 mg doses (92 hr while awake) for R.P. Repeat serum levels of methadone and its metabolite were then obtained over an &hour period. With this divided dosage regimen there were no major fluctuations for either subject in serum methadone levels. nor was there clinical evidence of
I
0
I
I
1
2
I
I
3
~
I
5
I
6
I
7
a
HOURS AFTER THE INJESTION OF lOOmg METHADONE Fig. 1. The time course of methadone and its metabolite in the serum of K.P. and R P. whcn they were each receiving a single daily dose of 100 mg. Study 1 refers to data presented by Kreek (1973): Study 2 to the work of Inturrisi and Verebely (1972).
693
Downloaded by [University of California, San Diego] at 00:07 20 April 2016
SERUM METHADONE
Fig. 2. The time course of methadone and its metabolite in the serum after clinical stabilization was attained.
an opiate withdrawal syndrome. The serum levels attained after stabilization are presented graphically in Fig. 2.
SUBSEQUENT CLINICAL COURSE OF K.P. AND R.P. After blood level stabilization was achieved, R.P. functioned well at work for the first time in a 2-year period, and K.P. was able to adequately care for her child (she had never been able to do so previously). The couple moved into a new house, and apparently completely severed their connections with the street drug scene. Unfortunately, after doing extremely well for 6 months, a friend of theirs took one of their take-home bottles of methadone. Concern about the possibility of ongoing diversion led us to deny them take-home privileges. They became angry over this and ultimately withdrew from the program. We feel that staff attitudinal issues probably played a major role in the rather unfortunate chain of events. Nursing staff was initially concerned and angry about handing out such large amounts of take-home methadone. They became much less angry when they saw how well the patients were doing, but continued to feel considerable resentment over what they perceived as inadequate involvement on their part in the initial decision-making process. When diversion occurred, they felt their earlier fears were justified, and a decision was made to revoke take-home privileges. More total participation of the entire staff in establishing a treatment plan would perhaps have resulted in a happier situation.
DISCUSSION Since Dole and Nyswander (1965) published their initial report, methadone maintenance has gained widespread acceptance as perhaps the
Downloaded by [University of California, San Diego] at 00:07 20 April 2016
604
WALTON, THORNTON, AND WAHL
most effective treatment modality yet developed for the hardcore heroin addict. Yet even the most devoted advocates of this approach generally acknowledge a “failure rate” of at least 205‘,. The present study raises the possibility that at least some of these individuals who drop out of treatment, and return to the use of heroin, d o so because they metabolize oral methadone in an “atypical” fashion. K.P. and R.P. were both articulate. patient individuals, able to inform us clearly about, and tolerate, significant degrees of physical discomfort during the period prior 10 stabilization. It seems likely that a significant number of other individuals may have a similar rapid decline in serum methadone levels several hours after ingesting a single daily dose, and cope with their discomfort by adding illicit drugs or dropping out of treatment. We suggest that the possibility of atypical methadone metabolism be considered when individuals complain of withdrawal symptoms and also demonstrate objective signs of the opiate withdrawal syndrome despite receiving what is generally considered to be an adequate daily dose of methadone. Serial serum methadone determinations would then be a logical next step for both diagnostic and management purposes. This study is based on only two subjects. Obviously more data are needed on the serum methadone levels of patients who are being maintained well and those who are not. The authors are currently engaged in this venture. Even the limited experience described above. however. justifies a more widespread utilization of serum methadone levels as ii laboratory tool in the assessment of patients who are not doing well on maintenance. REFERENCES DOLE. V.P.. and NYSWANDER. M.E. A medical treatment for diacetylmorphine (heroin) addiction: A clinical trial with methadone hydrochloride. J . A m . Med. A.c.roi,. 193: 646-050. 1965. DOLE, V.P.. NYSWANDER. M.E.. and KREEK. M.J. Narcotic blockage A r d i . h r t w ;\fed. 118: 3 0 4 ~309. 1966. GOLDSTEIN. A . Heroin addiction and the role of methadone in its treatment. Arc./?.Giw P.\~~/rirrrrj, 36: 311-297, 1972. INTURRISI, C.E., and VEREBELY. K . The levels of methadone in the plasma i n methadone mainlenance. C/i/i,Phnrniwol. T/ier. 13: 633-637. 1972. KREEK. M.J. Plasma and urine levels of methadone: Comparison following four medication l‘orms used in chronic maintenance treatment. A‘. Y . Siaic. .I. .Meti. pp 2773 2717. December 1973.
ISSN: 0020-773X (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/isum19
Serum Methadone as an Aid in Managing Methadone Maintenance Patients Ralph G. Walton, Thomas L. Thornton & Gerald F. Wahl To cite this article: Ralph G. Walton, Thomas L. Thornton & Gerald F. Wahl (1978) Serum Methadone as an Aid in Managing Methadone Maintenance Patients, International Journal of the Addictions, 13:5, 689-694, DOI: 10.3109/10826087809039295 To link to this article: http://dx.doi.org/10.3109/10826087809039295
Published online: 03 Jul 2009.
Submit your article to this journal
Article views: 7
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=isum19 Download by: [University of California, San Diego]
Date: 20 April 2016, At: 00:07
Downloaded by [University of California, San Diego] at 00:07 20 April 2016
The International Journal of the Addictions, 13(5), 689-694, 1978
Serum Methadone as an Aid in Managing Methadone Maintenance Patients Ralph G. Walton, M.D. Thomas L. Thornton, M.D. Gerald F. Wahl, M. Div. Jamestown, New York 14701
Abstract
Serial serum methadone levels were obtained in two patients who were experiencing significant difficulties (including subjective and objective evidence of the opiate withdrawal syndrome) while on methadone maintenance. A precipitous drop in blood levels of methadone was recorded 2 to 6 hours after ingestion. It was during this same time period that withdrawal symptoms were most severe. When methadone was administered on a divided dosage regimen, there was a dramatic clinical improvement in both patients and a marked flattening of the curve of serum methadone levels. This pilot. study suggests that the current practice of administering methadone as a single daily dose to all patients needs reconsideration; serial serum methadone levels may be helpful in determining which patients do better on a divided dosage regimen. 689 Copyright @ 1978 by Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher.
Downloaded by [University of California, San Diego] at 00:07 20 April 2016
690
WALTON. THORNTON, AND W A H L
The current practice of administering methadone as a single daily dose to patients on methadone maintenance is based upon the premise that the drug has a consistently long duration of action (at least 24 hours) (Goldstein, 1972). It is essentially accepted that the high-low-high-low fluctuations experienced by the addict on heroin d o not occur with methadone addiction (Dole et al., 1966). There are, however, relatively little data to support this belief. In our survey of the literature we found only two studies looking directly at the time course of methadone in the plasma of patients on maintenance. The work on Inturrisi and Verebely (1972) was based on five patients; that of Kreek (1973) on nine. Although the smooth curves which one can plot utilizing the data presented in these studies (Fig. 1 ) may well be correct for the majority of methadone maintenance patients, the small number of patients studied and clinical experience suggest that there may be significant individual variation in the time course of methadone metabolism. Because of the important treatment implications, this pilot investigation was conducted to determine if such v a ria t ion s ex ist .
METHODS Serial serum methadone levels of two individuals on methadone maintenance were studied. These subjects were selected from a group of81 such patients currently involved with the University of Rochester Drug Treatment Program because their histories suggested an unusual pattern of- response to opiates. R.P. is a 24-year-old White married male, and father of one son. He first became involved with drugs in 1968 when he began using psychedelics and marijuana. In 1970 he began using heroin by “snorting” initially, then “mainlining” after several months. He quickly developed a habit of 18 to 30 “bags” per day at a time when a typical bag often contained from 5 to 10 mg of heroin. I n presenting his history he repeatedly made the point that both he and his girlfriend (K.P., considered below) always required more heroin than their friends, and at any party were always the last ones to “nod off.” I n 1971 he began the first of multiple unsuccessful attempts at ambulatory detoxification with methadone. He allegedly combined his methadone with both heroin and barbiturates in an attempt to relieve what he described as “severe withdrawal symptoms.” Of note in his medical history is a splenectomy at age 4 for congenital
SERUM METHADONE
69 1
spherocytosis, and asthma since childhood, currently treated with Tedral. He has a twin sister who has no known history of drug abuse.
Downloaded by [University of California, San Diego] at 00:07 20 April 2016
K. P K.P. is a 25-year-old White female, mother of one son, and married to R.P. (described above). She first became involved with drugs as a 10th grade student when she began using amphetamines, psychedelics, and marijuana. At age 20 she began “shooting” methadone and cocaine, and then heroin. She claimed to always use more heroin than her addicted friends, and in fact became involved with R.P. because they shared the problem of needing more opiates than their peers, and always were the last ones to “nod off in a shooting gallery.” She is one of three siblings, and the only member of her family known to have a history of opiate addiction. During the first several months that they were on methadone maintenance, both R.P. and K.P. persistently complained that the drug “was not holding” them, despite eventually attaining a dose level of 100 mg/day. Aside from their subjective feeling of discomfort, each demonstrated clinical evidence of the opiate withdrawal syndrome within 4 to 6 hours after the ingestion of methadone. They exhibited diaphoresis, lacrimation, rhinorrhea, piloerection, skin pallor, and tachycardia. These signs and symptoms would appear very rapidly and increase in severity over the ensuing 18 hours before they were allowed their next daily dose. Each considered dropping out of the program because of the intense physical discomfort. When it became clear that both patients were about to return to the use of street heroin in an attempt to alleviate withdrawal symptoms, we obtained serial blood samples over an 8-hour period. The serum was analyzed by gas-liquid chromatography for methadone and the major methadone metabolite, dl-2-ethyl- 1,5-dimethyI-3,3-diphenyl1-pyrolidine. Blood was drawn at the time of ingestion of the morning dose of 100 mg of methadone and again at 1, 2, 4, 6, and 8 hours. Clinical observations of the patients’ status were recorded over this period. Serial blood levels were also obtained for each patient after “stabilization” was ultimately achieved (see below).
RESULTS Within the first 2 hours after ingesting 100 mg of methadone there was a rapid rise in the serum levels of methadone and its major metabolite.
Downloaded by [University of California, San Diego] at 00:07 20 April 2016
692
WALTON, THORNTON. AND W A H L
During the next 4 hours a precipitous fall in methadone levels was recorded for both subjects. The time course of these changes is presented graphically in Fig. 1. These data correlated well with what was observed clinically. The rapid fall in the blood level of methadone came at approximately the same time as the subjective and objective evidence of opiate withdrawal. On the basis of both the clinical and laboratory data, a decision was made to administer methadone on a divided dosage regimen to R.P. and K.P. (after obtaining the necessary approval from the appropriate state and federal agencies). The hope was that “evening out’’ the fluctuating blood levels would be reflected clinically by a cessation of withdrawal symptoms. Complex empirically based changes were made in both total daily dosage and the timing of methadone administration. The end point was determined by the patients’ subjective reports of comfort and stabilization. This occurred at a total daily dose of 180 mg, divided into three doses of 80,60, and 40 mg for K.P., and 260 mg, divided into three doses of 80,40, and 20 mg and eight separate 15 mg doses (92 hr while awake) for R.P. Repeat serum levels of methadone and its metabolite were then obtained over an &hour period. With this divided dosage regimen there were no major fluctuations for either subject in serum methadone levels. nor was there clinical evidence of
I
0
I
I
1
2
I
I
3
~
I
5
I
6
I
7
a
HOURS AFTER THE INJESTION OF lOOmg METHADONE Fig. 1. The time course of methadone and its metabolite in the serum of K.P. and R P. whcn they were each receiving a single daily dose of 100 mg. Study 1 refers to data presented by Kreek (1973): Study 2 to the work of Inturrisi and Verebely (1972).
693
Downloaded by [University of California, San Diego] at 00:07 20 April 2016
SERUM METHADONE
Fig. 2. The time course of methadone and its metabolite in the serum after clinical stabilization was attained.
an opiate withdrawal syndrome. The serum levels attained after stabilization are presented graphically in Fig. 2.
SUBSEQUENT CLINICAL COURSE OF K.P. AND R.P. After blood level stabilization was achieved, R.P. functioned well at work for the first time in a 2-year period, and K.P. was able to adequately care for her child (she had never been able to do so previously). The couple moved into a new house, and apparently completely severed their connections with the street drug scene. Unfortunately, after doing extremely well for 6 months, a friend of theirs took one of their take-home bottles of methadone. Concern about the possibility of ongoing diversion led us to deny them take-home privileges. They became angry over this and ultimately withdrew from the program. We feel that staff attitudinal issues probably played a major role in the rather unfortunate chain of events. Nursing staff was initially concerned and angry about handing out such large amounts of take-home methadone. They became much less angry when they saw how well the patients were doing, but continued to feel considerable resentment over what they perceived as inadequate involvement on their part in the initial decision-making process. When diversion occurred, they felt their earlier fears were justified, and a decision was made to revoke take-home privileges. More total participation of the entire staff in establishing a treatment plan would perhaps have resulted in a happier situation.
DISCUSSION Since Dole and Nyswander (1965) published their initial report, methadone maintenance has gained widespread acceptance as perhaps the
Downloaded by [University of California, San Diego] at 00:07 20 April 2016
604
WALTON, THORNTON, AND WAHL
most effective treatment modality yet developed for the hardcore heroin addict. Yet even the most devoted advocates of this approach generally acknowledge a “failure rate” of at least 205‘,. The present study raises the possibility that at least some of these individuals who drop out of treatment, and return to the use of heroin, d o so because they metabolize oral methadone in an “atypical” fashion. K.P. and R.P. were both articulate. patient individuals, able to inform us clearly about, and tolerate, significant degrees of physical discomfort during the period prior 10 stabilization. It seems likely that a significant number of other individuals may have a similar rapid decline in serum methadone levels several hours after ingesting a single daily dose, and cope with their discomfort by adding illicit drugs or dropping out of treatment. We suggest that the possibility of atypical methadone metabolism be considered when individuals complain of withdrawal symptoms and also demonstrate objective signs of the opiate withdrawal syndrome despite receiving what is generally considered to be an adequate daily dose of methadone. Serial serum methadone determinations would then be a logical next step for both diagnostic and management purposes. This study is based on only two subjects. Obviously more data are needed on the serum methadone levels of patients who are being maintained well and those who are not. The authors are currently engaged in this venture. Even the limited experience described above. however. justifies a more widespread utilization of serum methadone levels as ii laboratory tool in the assessment of patients who are not doing well on maintenance. REFERENCES DOLE. V.P.. and NYSWANDER. M.E. A medical treatment for diacetylmorphine (heroin) addiction: A clinical trial with methadone hydrochloride. J . A m . Med. A.c.roi,. 193: 646-050. 1965. DOLE, V.P.. NYSWANDER. M.E.. and KREEK. M.J. Narcotic blockage A r d i . h r t w ;\fed. 118: 3 0 4 ~309. 1966. GOLDSTEIN. A . Heroin addiction and the role of methadone in its treatment. Arc./?.Giw P.\~~/rirrrrj, 36: 311-297, 1972. INTURRISI, C.E., and VEREBELY. K . The levels of methadone in the plasma i n methadone mainlenance. C/i/i,Phnrniwol. T/ier. 13: 633-637. 1972. KREEK. M.J. Plasma and urine levels of methadone: Comparison following four medication l‘orms used in chronic maintenance treatment. A‘. Y . Siaic. .I. .Meti. pp 2773 2717. December 1973.
