Addiction Medicine, Article

Low dose intramuscular methadone for acute mild to moderate opioid withdrawal syndrome

a b s t r a c t

Study objective: To assess the efficacy of 10 mg intramuscular (IM) methadone in patients with Opioid withdrawal syndrome (OWS).

Methods: This was a prospective observational, convenience sample of patients presenting to the ED with mild to moderate OWS. Evaluations included the Clinical Opiate Withdrawal Scale (COWS), Withdrawal symptoms Scale (WSS), Altered Mental Status Scale (AMSS) and a physician assessment of the patient’s WSS (MDWSS). After en- rollment, 10 mg of IM methadone was administered and patients were reassessed at 30 min post-methadone ad- ministration. The primary outcome was the change in COWS at baseline and after methadone administration. Secondary outcomes were the differences between AMSS, and WSS post-methadone.

Results: Fifty-seven patients had COWS scores recorded at baseline and 30 min. Fifty-six had mild to moderate OWS. The COWS improved a mean of 7.6 after methadone administration (P b 0.001). The improvement was greater among patients presenting with moderate versus mild withdrawal (mean decrease = -9.1 vs. -5.5, P b 0.001). Patients were more likely to self-score themselves as having withdrawal compared to MDs (93.6% vs. 76.6% respectively, P = 0.027). Of the 62 patients with baseline and follow-up WSS by self-assessments, 69% im- proved post-methadone administration. In addition, the AMSS score remained the same or improved among 86% of cases with measurements at baseline and follow-up.

Conclusion: A single IM dose of 10 mg methadone in the ED reduces the severity of acute mild to moderate OWS by 30 min. Larger prospective, randomized controlled, and blinded studies would be needed to confirm these results.

(C) 2018



Dependence on opioids is an increasingly common occurrence that poses significant health concerns. In 2014, an estimated 1.9 million indi- viduals had a substance use disorder involving Prescription opioids and 586,000 had a substance abuse disorder involving heroin [1]. Many pa- tients present to the emergency department (ED) complaining of symp- toms of the opioid withdrawal syndrome (OWS) that typically results from intentional attempts at detoxification, lack of access to drugs as a result of changes in financial status or drug availability, or as the conse- quence of immobility, or incarceration.

The immediate goal of the treatment of acute OWS is to mitigate or prevent a severe withdrawal syndrome. The secondary goal is to pre- vent subsequent illicit use. Long-acting opioids, such as methadone or

* Corresponding author at: New York University School of Medicine, USA.

E-mail address: [email protected] (M.K. Su).

buprenorphine are generally prescribed in the outpatient setting and not typically prescribed in the ED; daily methadone is only dispensed by practitioners from licensed addiction treatment programs where it is used as a drug of choice because of its efficacy, long duration of relief from withdrawal, and high oral bioavailability [2,3]. Methadone is also indicated for inpatients who have a history of poor medical compliance when withdrawing from opioids or have significant medical and psychi- atric illnesses that would be exacerbated by withdrawal [4]. For treat- ment approaches to OWS that use an opioid, it is critical that practitioners administer a dosage of long-acting opioid that mitigates withdrawal symptoms but does not cause euphoria or adverse effects such as respiratory depression.

It is customary clinical practice at our institution to administer IM methadone at a relatively low dose (10 mg) to patients with acute OWS. The IM route of methadone assures delivery in patients who may have significant vomiting and/or diarrhea, and the low-dosage ad- ministration of 10 mg was enacted after some patients were adminis- tered their “reported” daily dose of methadone and subsequently suffered opioid-induced respiratory failure. The justification for the

0735-6757/(C) 2018

dose of 10 mg of IM methadone used in this study is that in methadone substitution for opioid detoxification, the test dose starts at 10 mg given orally, with additional doses of 10 mg to 20 mg given for signs and symptoms of OWS every 4 to 6 h in the first 24 h [4]. Oral methadone is not routinely administered at our institution for acute OWS because of concerns of Gastrointestinal symptoms secondary to OWS. Oral meth- adone is also avoided to prevent “cheeking”, the act of pretending to swallow the medication but in actuality, storing it in the cheek and later spitting it out for the purpose of diversion or abuse.

Despite decades of administration of 10 mg IM methadone based upon our institution’s standard practice for OWS, the efficacy and safety of this clinical practice has never been systematically evaluated. The goal of this study was to assess the efficacy of 10 mg of IM methadone for alleviating symptoms of acute OWS. The primary outcome measure was the change in OWS severity based on a standardized opioid with- drawal study instrument (COWS). The secondary outcomes included the assessment of the patient’s mental status (Altered Mental Status Scale; AMSS) after methadone administration and both self-reported and physician assessment of severity of withdrawal (Withdrawal Symp- toms Scale; WSS).


Study design and setting

This was a prospective study conducted at a large Inner city hospital ED with an annual census of approximately 100,000 patients. The study was conducted from July 2011 to September 2013.

Study population

Patients presenting to the ED with the subjective complaint or symptoms of OWS were evaluated by ED clinicians in standard fashion. Those patients identified by either ED Triage nurses with a self-reported chief complaint of “opioid withdrawal” or, deemed to be in OWS and candidates for methadone administration by ED clinicians, were approached for enrollment. Patient enrollment was not consecutive due to the lack of availability of research assistants (RAs) during all

hours of the day, and all days of the week during the study period. The RAs were trained by an emergency physician to record vital signs from one of the ED’s automatic vital signs reader (including pulse oximetry, blood pressure and temperature), and to record respiratory rate. They were also trained to use the OWS assessment tools and a sample of their charts was concurrently reviewed by one of the authors to assure accuracy. After the ED clinician made a decision to administer metha- done, the RAs informed patients of an ongoing study. Those expressing interest in participation were provided information by the RAs. The time at which the RA was notified was recorded (see Fig. 1) and denoted as “T-10 min”. A standardized verbal consent script was reviewed by the RAs with the patient who was then asked to summarize the study in order to assess understanding. Patients were informed that participa- tion in the study was voluntary and their answers to the questionnaire would not influence in any way the decision to treat with methadone, the dose that they were to receive, or the time to medication adminis- tration. Waiver of written consent was granted by both the Institutional Review Boards of both NYU School of Medicine and New York City Health and Hospital’s Corporation for the following reasons: 1) the study involved minimal risk – it was an observation of a practice that was already occurring; 2) the study could not be practically done if writ- ten consent was required – the time to go over a formal written consent is so long that it would be expected to delay the time to medication ad- ministration which would make most people decline to participate;

3) the greatest risk from study participation is breach of confidentiality, with the written record of consent being the only document that linked the participants to the study. Upon enrollment, subjects were assigned a unique identifying number specific to the study. Additionally, both IRBs permitted the inclusion of prisoners in the study after we demonstrated the high prevalence of OWS associated with incarceration.

Inclusion criteria

All patients aged 18 years and older who presented to the ED were eligible for this study. Patients were enrolled in the study if a treating physician determined patients were in OWS and the treating physician decided to give the patient methadone to treat OWS.

Fig. 1. Flowchart of patients included in the analysis of the primary and secondary outcomes. Of the 57 patients included in the analysis of the primary outcome, 51 (89%) had self-reported WSS scores and 50 (88%) had WSS determined by an MD. The secondary analysis was conducted on 47 patients who had follow-up WSS scores (taken 30 mins after methadone administration) determined by self-report and the treating physician. The baseline demographics of these patients are listed in Table 1.

Exclusion criteria

Patients who were b18 years of age, pregnant, or were determined by their treating physicians to be unable to understand the informed consent process were excluded. In addition, non-English speakers were excluded because the need for interpreter services could delay the study enrollment, and the subjective measures of OWS (see below) were not validated in other languages. Patients self-reported re- ceiving methadone for other indications (e.g., analgesia) were excluded.


During the time interval that normally occurs between a physician ordering methadone and its administration, the RAs conducted an initial assessment using a standardized study instrument (See Appendix), and recorded demographic information (age, gender and race) and history of opioid use (methadone vs heroin vs other, along with route and time of last use). Specifically, each patient was assessed at baseline using COWS, a validated 11-item rating system that is designed to be completed within 2 min by a trained observer [4,5]. The answers to the items were scored on a scale of 0 to 47, and OWS was subsequently classified as mild (5-12), moderate (13-24), moderately severe (25-36), or severe (N36). An initial set of vital signs, including heart rate, blood pressure, respiratory rate, and oxygen saturation, were taken from the patient’s ED chart.

Subjective assessment of the severity of withdrawal symptoms was evaluated using WSS, a 5-point Likert scale ranging from -2 to +2. A negative score on the WSS is correlated with increasing severity of OWS and a positive WSS score is correlated with opioid intoxication. With the assistance of the RA, each patient rated his/her own Symptom severity using the WSS, followed by the physician’s rating of WSS (the physician was blinded to the patient’s self-assessment and this rating was noted as MDWSS).

Lastly, an assessment of the patient’s mental status was performed using AMSS, a modified version of the Behavioral Activity Rating Scale and the Observer’s Assessment of Alertness/Sedation Scale [6,7]. The AMSS scores sedation and agitation on a scale with a range of -4 to 4 and has been previously used in the ED setting to quantify the CNS de- pressant effects of sedating agents and identify patients who are over- sedated [7,8]. On this scale, integer scores from -4 to 4 are given for re- sponsiveness, speech, facial expression, and eyes. A score of 0 is normal, negative numbers indicate sedation, and positive numbers indicate ag- itation [7]. For example, a score of 4 for responsiveness means the pa- tient is combative, violent, or out of control, while a score of -4 means the patient is unresponsive to mild prodding or shaking. For speech, a score of 4 indicates loud outbursts; -4 indicates few recogniz- able words. For facial expression, 4 represents an agitated facial expres- sion, and -4 marked relaxation (as seen in a slacked jaw). Finally, for the eyes, a score of 4 is normal, while a score of -4 corresponds to glazed and marked ptosis.

Methadone was administered by a nurse as per standard ED medica- tion administration protocols, and the dose and time of administration were recorded. Thirty minutes following the administration of metha- done, the RA repeated the COWS, AMSS, and WSS and performed a follow-up assessment of vital signs. The RA also asked treating clinicians for follow-up assessment of patients who remained in the ED every 30 min, or until patients were discharged. Additional details of the clin- ical encounter were recorded from the patient’s ED paper chart, includ- ing final diagnosis, final disposition (discharge vs admission vs leaving against medical advice), the need for repeating dosing of an opioid, and the type and dose of any other medications administered. The deci- sion to discharge, and timing of discharge of patients was entirely based on the treating physician’s judgment and was not impacted by the study enrollment. Furthermore, patients could end their participation at any time and be discharged from the ED if deemed safe by clinicians. If

patients were admitted to the hospital and transported out of the ED, no further information was obtained.

All adverse events were recorded by the RAs who were also instructed to notify treating physicians or nurses for hypoxia (defined as O2 saturation b 95% or 5% change from baseline), respiratory depres- sion (defined as a respiratory rate b 12 breaths per minute) or signifi- cant CNS depression (an AMSS score <= -2). Similarly, if medical staff noted any adverse events, the RAs were informed.

Statistical analysis

Primary outcome: change in COWS score

For purposes of this analysis, all COWS scores were treated as contin- uous variables and all scores below five were considered to indicate ab- sence of OWS. For each patient, we subtracted COWS at first assessment after methadone administration from the COWS at baseline (prior to methadone administration). We then tested whether the average dif- ference was significantly greater than zero using a one-sided paired stu- dent t-test. We use a one-sided test based on current understanding that there is no biological plausibility by which a full opioid agonist could exacerbate withdrawal.

Secondary outcomes: AMSS and WSS

For patients included in the analysis of primary outcomes, we exam- ined two other assessment scores. First, we evaluated changes in AMSS score to measure the possibility of over sedation following the adminis- tration of methadone.

Second, we examined the WSS score as a subjective measure of withdrawal symptoms. We compared baseline WSS scores and changes in scores as determined by the treating physician and the patients themselves (self-report). The distribution of baseline scores (physician vs self-reported) were examined to calculate a proportion of patients who were scored as experiencing severe (WSS = -2), mild (WSS =

-1) or no withdrawal symptoms (i.e., a WSS score N0) at baseline. We dichotomized the baseline WSS score to reflect any withdrawal symptoms (yes/no) and tested for a difference at baseline using a McNemar’s chi-squared test.

We also evaluated the change in withdrawal score as determined by the treating physician compared to the self-reported score. First, we de- veloped “transition matrices” for each evaluator type. For each baseline WSS score (or state) the transition matrix represents the probability of moving to another state after the methadone administration. Second, among patients with a baseline WSS of -2 or -1, we calculated the overall proportion of patients whose WSS score improved after metha- done administration. These results were compared between the evalu- ator type (physician or self-report). Finally, we examined whether the WSS captured a similar amount of change in withdrawal symptoms re- gardless of who evaluated the patient (physician or self-report).


Characteristics of study participants

Initially, 124 patients were approached to participate. Of these, 22 (17.7%) were excluded for having no withdrawal symptoms at baseline (COWS b 5) or no COWS score recorded at baseline (see Fig. 1); 14 (9.7%) more were excluded because the dosage given was not docu- mented; 6 additional patients (4.8%) were excluded because they re- ceived doses other than 10 mg IM (one given 5 mg, 4 given 20 mg, one given 70 mg). Of the remaining 82 patients with OWS who received 10 mg IM methadone and enrolled in the study, 25 (30.5%) were ex- cluded because of no follow-up assessment after methadone adminis- tration as a result of either being discharged or refusal to continue to participate. Thus overall, 46% of (57/124) of patients approached to par- ticipate were ultimately included in the analysis of primary outcome. These patients are summarized in Table 1.

Table 1

Baseline demographics of patients included in the analysis of primary outcomes.











Median (range)






























Type of opioid Methadone only



Methadone and heroin



Methadone, heroin and other






Heroin only



Oxycodone only



Heroine and oxycodone



Methadone dose (for those using methadone alone and with other opioid)

Median (range) 80


Number formally enrolled in a clinic (among methadone users)







Not recorded



Primary outcome

Of the 57 patients included in the analysis of the primary outcome, 98% (56/57) had a baseline COWS consistent with mild or moderate se- verity OWS (28 with mild and 28 with moderate withdrawal) and one patient (1.8%) had moderately severe symptoms. The COWS score at the first assessment after methadone administration was, on average,

7.6 points (standard error = 0.76) lower than what was recorded at

baseline (P b 0.001). The average drop in score was less in patients pre- senting with mild withdrawal (mean = -5.5, SD = 3.2) compared to moderate withdrawal (mean = -9.1, 6.5, P b 0.001). The only patient who was classified as having moderately severe withdrawal at baseline had a 23-point drop in the COWS score after administration of metha- done. The individual changes in COWS score from baseline to the first follow-up are shown in Fig. 2. Although our initial goal was to assess the patients after methadone administration every 30 min, for a mini- mum of 3 assessments, statistical analysis was not carried out for data points after 30 min because of attrition.

Secondary outcomes: change in AMSS and WSS

Of the 57 participants from the primary outcome analysis, 51 (89%) had AMSS scores at baseline and follow-up. Of these, 47% (24/51) had an AMSS score of zero at baseline and follow-up, 24% (12/51) of AMSS scores started away from zero but were zero at follow-up, 16% (8/51) had no change in their AMSS score and 14% (7/51) had a worsening score and became more agitated.

Patients were more likely to score themselves as being in with- drawal after receiving methadone in the ED (i.e., a score of b0) com- pared to the physician’s assessment (93.6% vs. 76.6% respectively, P = 0.03). In addition, an assessment of “severe withdrawal” after metha- done administration was more common based on patient self-

Image of Fig. 2

Fig. 2. Change in COWS score from baseline (prior to methadone administration) to first assessment post-methadone administration. Each one of the solid lines represents the change for one patient. Lines are colored according to symptom severity at baseline. The thick dotted lines represent the average change for each of the severity categories.

assessment compared to the physician’s assessment (61.7% vs 10.6% re- spectively, P b 0.001), whereas “mild withdrawal” was less common by patients’ compared to physicians’ assessment (31.9% vs. 66.1%, P-value b 0.001). Table 2 shows the transition matrices for the WSS as determined by self-assessment and physicians. Based on self-assessment, patients starting with a score of -2 were slightly but not significantly more likely to improve compared to scores starting at -1 (86% vs 67%, P = 0.24).

The percentage of patients that showed symptom improvement was statistically similar regardless of assessment (74% by self-report vs. 66.0% by physicians, P-value = 0.43). In fact, for 55% of patients the self-assessment and physician’s assessment agreed in seeing symptom improvement; in 15% of patients, evaluators agreed in seeing no change; 30% of the evaluations didn’t coincide (Table 2).

With respect to safety, patients were observed for possible adverse events by the nursing staff, the treating physicians, and the research as- sistants. Any adverse event that occurred was documented as per the study protocol. No adverse effects were reported and no patients devel- oped excessive sedation or respiratory depression.


This study demonstrated that patients with OWS improved a mean of 7.6 units on the COWS at 30 min after 10 mg IM methadone admin- istration (P b 0.001). Based on our analysis, this was a statistically signif- icant improvement. Additionally, since the COWS can discriminate the clinical severity of withdrawal, a reduction in 7.6 units is likely to move most patients to lower degree of severity. In fact, 47 of the 57 pa- tients in the primary analysis fell by at least one severity grade on the COWS scale.

In our study, we also noted that patients routinely self-assessed the severity of their withdrawal to be greater compared to the treating cli- nician. This discrepancy between patients’ and clinicians’ assessment of OWS reinforces that in addition to the tangible physical component of OWS there is a significant psychological component that is likely un- derappreciated by clinicians. Alternatively, it is possible that patients over-report their symptoms because of their desire to receive therapy. Compared to clinicians, the majority of the patients believed that meth- adone was less effective for the severity of their withdrawal, but the pa- tients showed statistically significant improvements on all three scales

Table 2

Transition matrices for WSS self-assessment (A) or MD (B). Each cell represents, for a given baseline score (shown by the row), the percentage of people who ended up with a given post-methadone score (shown by the column).

Scoring by self -assessment

(N = 47)

Post Methadone

-2 -1 0 1 2 N

-2 0.14 0.62 0.24 0 0 29

-1 0 0.33 0.60 0 0.07 15


0 0 0 1 0 0 1

1 0 0 1 0 0 1

2 0 0 0 1 0 1

N 4 23 18 1 1 47

MD scoring (N = 47)

Post Methadone

-2 -1 0 1 2 N

-2 0 0.6 0.4 0 0 5

-1 0 0.16 0.84 0 0 31


0 0 0 1 0 0 10

1 0 0 1 0 0 1

2 0 0 0 0 0 0

N 0 8 39 0 0 47

The numbers in the cells represent the proportion of patients who started in the particular WSS indicated in the row and ended up in the WSS indicated in the column header.

of opioid withdrawal used in this study, and all were ultimately deemed stable for discharge.

There were important limitations in the study. First, at our institu- tion many patients are in police custody and often brought to the ED for short periods of time prior to incarceration while awaiting arraign- ment. Because patients were mostly men and mostly imprisoned or in police custody, this might limit the generalizability of our results to other settings. However, it is of utmost importance for practitioners to provide treatment for acute or impending OWS in these incarcerated patients considering the fact that they will not have access to opioids for an indefinite period of time. This is even more relevant when consid- ering that patients may be unsupervised during the period of acute in- carceration. Determining a routinely effective dose may also aid practitioners in their discussion with patients who may initially ques- tion the dosage of methadone they are administered, leading to in- creased patient satisfaction, better physician-patient relationships, and increasED throughput. Low dose methadone given as a 10 mg IM dose appears to be appropriate for this patient population, especially when compared to placebos and to ?2-adrenergic agonists (e.g., clonidine). Controlled trials show that for managing withdrawal symptoms and retaining patients in treatment programs, methadone tapering is supe- rior to placebo and ?2-adrenergic agonist-based regimens when given to patients who misuse other opioids [5]. Compared to ?2-adrenergic agonists, there are fewer adverse side effects, and the onset of with- drawal symptoms and signs occurs later with methadone [3]. With- drawal treatment programs using methadone also had similar completion rates as those using ?2-adrenergic agonist-based regimens, despite having a greater duration of treatment [3]. Furthermore, due to the lack of adverse events, including respiratory depression, recorded following low dose methadone administration, and significant improve- ment in the COWS score at initial assessment, we believe low dose methadone is an effective treatment for OWS.

Second, the study was observational (non-randomized, no control

group) and the sample size was too limited to stratify the data based the type of opioid used, limiting the ability for researchers to determine whether users of a specific opioid respond better to 10 mg IM metha- done than others. It is also possible that other drugs or other medica- tions used by the participants (e.g., ethanol, sedative hypnotics, antidepressants, etc.) could have either blunted or enhanced the effects of methadone administered. Third, one-third of the patients either re- fused to continue to participate in the study or were discharged from the ED after the first assessment at 30 min. There was insufficient data beyond 30 min after patient enrollment to determine efficacy of the 10 mg IM methadone. For an opioid with a long half-life such as meth- adone, symptoms of opioid withdrawal typically begin 36 to 48 h after the last dose [3]. Because there were insufficient data beyond 30 min, it is unclear whether any benefits were maintained for the subsequent withdrawal and their duration of benefit. Similarly, there were no data available regarding adverse outcomes beyond the participants’ ED stay. While the protocol for the incarcerated population requires the

police to bring patients back to the ED for any Medical issues, it is un- known whether adverse events occurred because there were no record- ings of patients returning as “bounce backs”. It is possible that participants did “bounce back” without the study investigators being made aware.

Additionally, although we noted a statistically significant de- crease in the COWS score after methadone administration, it is not entirely clear if a specific reduction in the absolute COWS score can be considered clinically significant. The COWS score is an objective measure of OWS that classifies patients into four classes: mild, mod- erate, moderately severe and severe withdrawal. For the purposes of this study we considered a fall in COWS gradation to indicate clinical improvement as it is intuitive that it preferable to be in mild with- drawal compared to moderate withdrawal. In fact, recently, COWS has been used clinically during buprenorphine induction. When a patient has a COWs above 6, buprenorphine may be safely adminis- tered to patients without the concern for precipitated OWS [9]. Pre- cipitated OWS is associated with intense clinical manifestations that is abrupt in onset and can cause significant patient discomfort. Fu- ture studies on patients with more severe OWS should be conducted to determine if the COWS score should be used to monitor clinical re- sponse to OWS treatments.

Last, we believe that low dose methadone is a short-term effective therapy in select ED patients, however we realize this is a temporary fix to the problem and do not consider this to be adequate Long-term treatment for a complex problem such as OWS. Our study was also lim- ited because patient follow-up beyond 30 min could not be obtained in a large proportion of our patients. Although buprenorphine induction in the ED would be our preference, its use would be better for sicker pa- tients (i.e., those with moderate to severe OWS) and require a longer period of ED observation [10]. Our future practice will likely involve the replacement of low dose methadone with buprenorphine induction and baseline data on low dose methadone will also serve as a historical control for future studies.

Despite these limitations, the study did show both a subjective and an objective benefit in OWS. A single dose of 10 mg IM methadone ap- pears to be a safe and easily administered remedy for OWS. In conclu- sion, we believe that 10 mg IM methadone is a reasonable treatment for patients in acute opioid withdrawal, regardless of type, route and dose of Opioid abused. Further research is necessary to determine whether this dose is safe and effective in diverse patient populations and if the effects are long lasting.

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajem.2018.02.019.


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