Exploring the relationship between perceived inter-dose opioid withdrawal and patient characteristics in methadone maintenance treatment

doi:10.1016/j.drugalcdep.2009.07.003

Drug and Alcohol Dependence

Volume 105, Issue 3, 1 December 2009, Pages 209-214

https://doi.org/10.1016/j.drugalcdep.2009.07.003 Get rights and content

Abstract

Background

Despite clinical optimization of methadone doses, as many as 53% of patients experience significant and unacceptable levels inter-dose opioid withdrawal some of the time. Little is known about the relationship between perceived inter-dose opioid withdrawal and patient characteristics in methadone maintenance treatment.

Methods

Ninety stabilized MMT patients were recruited and divided into three satisfaction groups (holders (H), partial holders (PH), and nonholders (NH)) based on their perceived opioid withdrawal as assessed by a guided self-report process. A battery of subjective assessments was administered during the approximate trough methadone condition. The primary measures were the Subjective Opioid Withdrawal Scale (SubOWS), Hopkins Symptom Checklist-90 (SCL-90), Obsessive–Compulsive Drug Use Survey (OCDUS), Profile of Mood States (POMS), and Neo Personality Inventory (NEO).

Results

Nonholders experienced more opioid withdrawal (SubOWS—NH: 22.0 ± 8.8 vs. PH: 12.2 ± 8.2 vs. H: 9.3 ± 10.0, p < 0.001) and craving (OCDUS—NH: 11.4 ± 8.8 vs. PH: 6.4 ± 6.9 vs. H: 6.5 ± 6.2, p = 0.016). Holders experienced less Obsessive/Compulsive psychological distress (SCL-90—NH: 15.3 ± 8.1 vs. PH: 12.3 ± 7.3 vs. H: 6.6 ± 5.1, p < 0.001), Depression/Dejection (POMS—NH: 19.7 ± 13.7 vs. PH: 17.2 ± 13.2 vs. H: 7.9 ± 10.4, p = 0.002), and neurotic personality (NEO—NH: 63.3 ± 12.3 vs. PH: 60.9 ± 10.0 vs. H: 54.0 ± 8.8, p = 0.006). Partial holders had a less agreeable personality (NEO—NH: 44.2 ± 8.6 vs. PH: 38.0 ± 10.6 vs. H: 47.6 ± 11.7, p = 0.002).

Conclusions

Physical opioid withdrawal is an important factor in understanding patient satisfaction with MMT. However, patient characteristics, such as level of psychological distress and negative mood, may also need to be considered because of their relationship with perceived inter-dose opioid withdrawal symptoms and patient satisfaction.

Introduction

Opioid addiction is a chronic relapsing disorder that is associated with significant social and health consequences, including high levels of unemployment, criminal activity, reliance on social services and transmission of blood-borne infections (Fischer et al., 1999, Office of National Drug Control Policy, 2001). Opioid substitution therapy, with methadone or buprenorphine, is often the first line of treatment for individuals addicted to opioids. Methadone, in particular has been used for many decades for this indication (Dole and Nyswander, 1965, Dole and Nyswander, 1966).

Treatment response to opioid substitution therapy is typically measured using objective outcomes such as, retention in treatment and reduction in opioid-positive urine screens. Less frequently, patient satisfaction with treatment is considered. However, patient satisfaction with treatment has been shown to be a predictor of treatment retention (Villafranca et al., 2006) and to be associated with abstinence from substance use (Carlson and Gabriel, 2001), therefore investigating the features and influencing factors of patient satisfaction is warranted. Satisfaction with treatment may involve many aspects of treatment, for example, satisfaction with access to services, satisfaction with the effectiveness of services, and global satisfaction with care (Carlson and Gabriel, 2001). Patient satisfaction specifically as it relates to the effectiveness of methadone pharmacotherapy can be associated with perceived opioid withdrawal symptoms as experienced by the patient and can reflect the degree to which individuals feel that their pharmacotherapy needs are being met, and the level of contentment they find with their substitution therapy.

Seventy years ago, Kolb and Himmelsbach importantly noted that some patients experiencing opioid withdrawal show many objective signs of withdrawal but complained little; while others show no objective signs but present as restless, pained, and nervous (Kolb and Himmelsbach, 1938), suggesting that factors other than physical withdrawal may influence perceived opioid withdrawal and consequently patient satisfaction with treatment. Despite attempts at dosage optimization clinically, as many as 53% of patients experience significant and unacceptable inter-dose withdrawal at least some of the time and 34% of patients experience this frequently or all of the time (Dyer and White, 1997). Dyer and White (1997) termed those who complained of withdrawal frequently or all the time as ‘nonholders’; and the rest of patients were termed ‘holders’. Dyer and colleagues evaluated the relationship between mood and patient satisfaction with treatment in methadone maintenance patients. They found that mood disturbance, in individuals without psychiatric disorders, was associated with patient dissatisfaction with treatment. That is, nonholders experienced greater mood disturbance with maximum differences during the trough methadone condition (i.e., the time when the lowest methadone concentration is attained over the dosing interval, which is just before the next dose is taken) (Dyer et al., 1999). In a recent study in our laboratory we examined the influence of major depressive disorder on methadone pharmacological properties in stabilized methadone maintenance treatment patients. We found that methadone maintenance treatment patients with comorbid major depressive disorder experienced greater levels of opioid withdrawal compared to methadone patients without comorbid major depressive disorder. Further, opioid withdrawal symptom severity was proportional to depression severity (Elkader et al., 2009).

We also noted that when methadone maintained patients were asked to self-identify as holders or nonholders, they often had difficulty making a clear designation, and considered their situation to be more complex than the dichotomous categorization allowed (Elkader et al., 2009). In light of these observations, we hypothesized that factors other than physical opioid withdrawal symptoms may influence patients’ satisfaction with methadone treatment, and specifically that psychological factors would have an impact. The purpose of this study was to systematically evaluate factors that could impact or influence patient satisfaction with opioid substitution therapy in order to better characterize these patients.

Section snippets

Study participants

This study was approved by the Centre for Addiction and Mental Health (CAMH) Research Ethics Board. Participants were recruited from the CAMH and other methadone clinics in the Greater Toronto Area with posted flyers. Of the total of 205 individuals who responded to the advertisement, 183 were able to be contacted and 90 passed the telephone screening and provided informed consent. All but one of the study participants completed the entire study day protocol. This participant was not

Study participants

A total of 90 participants (25 holders, 35 partial holders, and 30 nonholders) completed the study protocol. See Table 1 for a summary of patient characteristics. While partial holders were in treatment for less time than patients in the other groups, they were stabilized in treatment (that is, they had been in treatment for a mean of more than four consecutive years and on the same dose for a mean of nearly eight consecutive months). Also a disproportionately greater number of males were

Discussion

In this study we characterized methadone maintenance treatment patients with respect to patient satisfaction with treatment. Patient characteristics in this study (age, gender and dose) are similar to those reported in previous studies from the Centre for Addiction and Mental Health (Brands et al., 2002, Brands et al., 2003) and from those in other methadone maintenance clinics in Canada and other countries (Teplin et al., 2007, Anderson and Warren, 2004, Peles et al., 2008, Harris et al., 2006

Role of funding source

No outside funding is declared.

Contributors

All authors constructed the research design and analytic plan. Alexander Elkader implemented the study protocol, including recruiting the study subjects and conducting the study sessions. He also undertook the statistical analysis, and wrote the first draft of the manuscript. This work was completed as part of his PhD program. Beth Sproule supervised and contributed to all components of the research. All authors materially participated in the research and/or manuscript preparation. All authors

Conflict of interest

All authors declare that they have no conflicts of interest.

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Psychological factors seem to play a key role in the severity of withdrawal symptoms. Since greater intensity of these symptoms increases the risk of developing POUD, knowing the factors associated with withdrawal may be useful in developing preventive psychological interventions.
Day-to-day opioid withdrawal symptoms, psychological distress, and opioid craving in patients with chronic pain prescribed opioid therapy
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The contribution of withdrawal symptoms to psychological distress has been well-documented in the addiction literature (Le Moal and Koob, 2007), but this had remained largely unexplored among patients with chronic pain prescribed long-term opioid therapy. In the context of our study, it is possible that the aversiveness and unpleasantness of opioid withdrawal symptoms (Elkader et al., 2009; Koob et al., 1989) led to increases in negative affect and catastrophic thinking, which in turn contributed to elevations in opioid craving. On days when opioid craving was high, it is possible that patients craved the alleviation of aversive/unpleasant feelings associated with opioid withdrawal (Ballantyne, 2017; Juurlink, 2017) as well as the attenuation of psychological distress (Ballantyne and Sullivan, 2017; Kirsh et al., 2007; Passik and Kirsh, 2011).
Research has shown that opioid craving is one of the strongest determinants of opioid misuse in patients with chronic pain. To date, however, little is known on the factors that contribute to opioid craving in these patients. It is possible that patients’ physical dependence to opioids, manifested by opioid withdrawal symptoms in between daily opioid doses, contribute to opioid craving. Physical dependence symptoms might also lead to psychological distress, which in turn might contribute to opioid craving. The first objective of this study was to examine the day-to-day association between opioid withdrawal symptoms and opioid craving among patients with chronic pain. We also examined whether negative affect and catastrophic thinking mediated this association.
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Day-to-day elevations in opioid withdrawal symptoms were associated with heightened opioid craving (p < .001). Results of a multilevel mediation analysis revealed that this association was mediated by patients’ daily levels of negative affect and catastrophizing (p < .001).
Our study provides valuable new insights into our understanding of factors that may contribute to prescription opioid craving among patients with chronic pain.
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Psychological and physiological stress negatively impacts early engagement and retention of opioid-dependent individuals on methadone maintenance
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La atención psicosocial y el tratamiento de mantenimiento con metadona (TMM) son las estrategias preferidas para el manejo de adictos a heroína, pero los resultados siguen siendo insatisfactorios, lo que justifica la búsqueda e intervención sobre los factores que influyen en la respuesta al tratamiento.
Con el propósito de determinar la contribución de una serie de variables demográficas, clínicas y genéticas en las concentraciones séricas y la respuesta a la metadona, estudiamos a pacientes del TMM que estuvieran recibiendo metadona con supervisión y sin cambios en las dosis por lo menos durante las últimas 2 semanas. Se les registró edad, sexo, índice de masa corporal (IMC), tiempo de abuso de heroína, adicción a otras drogas, antecedentes delictivos, dosis diaria actual de metadona, tiempo de permanencia en el TMM, comorbilidad y comedicación. Se les tomaron muestras de sangre para determinar concentraciones séricas de metadona racémica y sus enantiómeros R- y S-, y para la tipificación de alelos candidatos de los genes POR, CYP2B6, ABCB1, GRIN1, OPRM1, SLC6A3, DßH y ARRB2, todos ellos asociados con el metabolismo, la distribución tisular y el mecanismo de acción de la metadona. La cuantificación de metadona se hizo mediante HPLC-DAD y la detección de los marcadores genéticos por los métodos de PCR en tiempo real y VNTR.
Se incluyó a 80 personas de 23,5 ± 5 años (el 86% varones), todos policonsumidores de sustancias adictivas, el 60% con antecedentes delictivos, con 5,1 ± 2,9 años de consumo de heroína y 5,3 ± 4 meses de ingreso al TMM, con 41 ± 12 mg/día de metadona tomada con supervisión. Las concentraciones valle de RS-, R- y S-metadona fueron, respectivamente, 168 ± 77, 84 ± 40 y 84 ± 42 ng/ml. Todos los genotipos estuvieron en equilibrio de Hardy-Weinberg. Las dos pruebas de orina fueron negativas para heroína en el 61,3% (49/80) de los voluntarios; el descenso en el consumo de cocaína/basuco fue del 83%; el de marihuana, del 30% y el de otros psicoactivos (inhalantes, benzodiacepinas, anfetaminas) bajó a cero, mientras el consumo de tabaco permaneció en el 93,5% (75/80). Las concentraciones de metadona racémica y sus enantiómeros se correlacionaron significativamente con las dosis diaria del fármaco, pero ninguna de las demás variables demográficas, clínicas o genéticas incidió en la concentración sérica de metadona. En cuanto a los resultados del TMM, los no consumidores y los consumidores ocasionales de heroína, así como los que abandonaron el consumo de otros psicoactivos y los que no, tuvieron características similares con respecto a las variables demográficas, genéticas y clínicas, incluidas las concentraciones sanguíneas de metadona, con excepción de los individuos que no disminuyeron el consumo de otros psicoactivos distintos de heroína, quienes tuvieron significativamente (p = 0,03) mayores concentraciones sanguíneas de S-metadona que quienes sí abandonaron el consumo.
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Psychosocial care and methadone maintenance treatment (MMT) are the preferred strategies for the management of heroin addicts, but the results are still unsatisfactory, justifying the search and intervention of the factors influencing the response to treatment.
In order to determine the contribution of demographic, clinical and genetic variables on serum concentrations and response to methadone, we investigated patients on MMT, who were receiving methadone in supervised and unchanged doses at least during the previous two weeks. The age, gender, body mass index (BMI), duration of heroin abuse, addiction to other drugs, criminal background, current daily methadone doses, time spent in the TMM, comorbidity and concomitant medication were recorded. Blood samples were taken for the determination of serum levels of racemic methadone and its R and S-enantiomers, and for typing of candidate alleles of POR, CYP2B6, ABCB1, GRIN1, OPRM1, SLC6A3, DßH and ARRB2 genes, all associated with the metabolism, tissue distribution and mechanism of action of methadone. Methadone quantification was by HPLC-DAD, and the detection of genetic markers by Real Time PCR and VNTR methods.
A total of 80 subject volunteers were enrolled, with a mean age of 23.5 (5) years (86% male), all of them were addicts of multiple drugs, 60% with a criminal background, 5.1 (2.9) years taking heroin, and 5.3 (4) months on MMT, and taking a supervised dose of 41 (12) mg/day methadone. The (R), (S) and (R, S) methadone enantiomer trough plasma levels were, 84 (40), 84 (42), and 168 (77) ng/mL, respectively. All genotypes were in Hardy-Weinberg equilibrium. The two urine tests were negative for heroin in 61.3% (49/80) of the volunteers, the decline in cocaine/crack use was 83%, 30% of marijuana, and other psychoactives (inhalants, benzodiazepines, amphetamines) decreased to zero, while the consumption of snuff remained at 93.5% (75/80). Blood concentrations of racemic methadone and its enantiomers were significantly associated with the dose/day of the medication, but none of the other demographic, clinical or genetic variables impacted on serum levels of methadone. As for the results of the MMT, non-users and occasional users of heroin, as well as those who stopped taking other psychoactive drugs, and the ones who did not, were similar as regards the demographic, genetic and clinical variables. This included the blood metahdone concentrations, except for individuals who did not reduce their consumption of other psychoactives other than heroin, who had significantly (P = .03) higher blood levels of S-methadone, compared with those who did stop taking them.
There was a significant reduction in the consumption of heroin and other psychoactives, and social rehabilitation of patients. However, the extensive overlap between effective and ineffective doses of methadone suggests the presence of personal and social variables that transcend the simple pharmacological management. These probably need to be addressed more successfully from the psychosocial features, particularly as regards to identifying and overcoming relapse-trigger experiences, as well as certain features of the patient, such as their psychological distress level or their psychiatric disorders.
Elevated pain sensitivity in chronic pain patients at risk for opioid misuse
2011, Journal of Pain
This study employed quantitative sensory testing (QST) to evaluate pain responses in chronic spinal pain patients at low risk and high risk for opioid misuse, with risk classification based on scores on the Screener and Opioid Assessment for Patients with Pain-Revised (SOAPP-R). Patients were further subgrouped according to current use of prescription opioids. Of the 276 chronic pain patients tested, approximately 65% were taking opioids; a median split was used to further categorize these patients as being on lower or higher doses of opioids. The high-risk group (n = 161) reported higher levels of clinical pain, had lower pressure and thermal pain thresholds at multiple body sites, had lower heat pain tolerance, and rated repetitive mechanical stimuli as more painful relative to the low-risk group (n = 115; P’s < .01). In contrast, QST measures did not differ across opioid groups. Multiple linear regression analysis suggested that indices of pain-related distress (ie, anxiety and catastrophizing about pain) were also predictive of hyperalgesia, particularly in patients taking opioids. Collectively, regardless of opioid status, the high-risk group was hyperalgesic relative to the low-risk group; future opioid treatment studies may benefit from the classification of opioid risk, and the examination of pain sensitivity and other factors that differentiate high- and low-risk groups.
This study demonstrates that chronic spinal pain patients at high risk for misuse of prescription opioids are more pain-sensitive than low-risk patients, whether or not they are currently taking opioids. Indices of pain-related distress were important predictors of pain sensitivity, particularly among those patients taking opioids for pain.

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Exploring the relationship between perceived inter-dose opioid withdrawal and patient characteristics in methadone maintenance treatment

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Study participants

Study participants

Discussion

Role of funding source

Contributors

Conflict of interest

Drug Alcohol Depend.

Drug Alcohol Depend.

Addict. Behav.

Addict. Behav.

J. Subst. Abuse Treat.

J. Subst. Abuse Treat.

J. Pain Symptom Manage.

Pain

Pain

Behav. Res. Ther.

Drug. Alcohol Depend.

Client retention in the British Columbia methadone program, 1996–1999

Can. J. Public Health

The development of an Opiate Withdrawal Scale (OWS)

Br. J. Addict.

Impact of methadone program philosophy changes on early treatment outcomes

J. Addict. Dis.

Patient satisfaction, use of services, and one-year outcomes in publicly funded substance abuse treatment

Psychiatr. Serv.

Assessment of the abuse liability of buspirone in recreational sedative users

J. Clin. Psychiatry

The role of psychiatric disorders in predicting drug dependence treatment outcomes

Am. J. Psychiatry

Normal personality assessment in clinical practice: the NEO Personality Inventory

Psychol. Assess.

Revised NEO Personality Inventory (NEO-PI-R) and NEO Five-Factor Inventory (NEO-FFI) professional manual

SCL-90 R (Revised) Version Manual-I

The Hopkins Symptom Checklist (HSCL). A self-report symptom inventory

Behav. Sci.

A medical treatment for diacetyl-morphine (heroin) addiction

JAMA