[Feature image via WeeMikey]
In my current practise environment, a LOT of my patients are on long term methadone replacement. Indeed such is the unique nature of our local population that there’s quite a lot of research into intravenous drug use and even HIV. In a few years if my smart colleague gets all the data together, we’ll hopefully be able to tell you exactly what proportion of people are on methadone attending the ED.
It’s so ubiquitous amongst our patients that most don’t even consider it a medication. When you ask someone one if they take any regular medication, people will frequently not mention the fact that they take the OCP. The same goes for methadone, and even LMWH which a lot of our patients receive daily for their IDU (injecting drug use) associated VTE (venous thromboembolism).
Methadone is a fascinating little drug, both in regular use and in overdose so here’s a summary:
- developed in Germany during world war II as a synthetic alternative to morphine as morphine was hard to obtain
- used for opioid treatment programs, chronic pain, and palliative care.
Use in opioid treatment programs
- usually provided as a directly observed medication in a pharmacy or drug clinic. In our part of the world it’s green like fairy liquid. The concentration can be altered so that even when receiving the same volume a bigger does is given.
- The aim is usually long term rather than a short term detox. To come off methadone is normally a process that is meant to take months-years.
- There is good evidence of effect on reduced relapse and possibly even mortality
- mu opioid receptor agonist
- NMDA receptor antagonist. The NMDA part is thought to attenuate opioid tolerance
- Volume of distrubution 4 L/kg. This is realatively large and all you need to know is that is widely distributed in the tissues. This is one of the reasons for its long half life as it leaks back into the circulation from the tissues over time.
- Elimination: mainly by oxidative biotransformation – which means it’s coverted into lots of metabolites, some active, some inactive. The metabolites and indeed methadone itself mainly leave in the wee wee.
- of note there are, as usual, some problems with the urine testing. Some urine tox kits will test methadone separately from other metabolites. This is obviously a good way to monitor abstinence from illicit opioids. But like all urine testing – you need to know your test characteristics.
- Half-life ranges from 5-130 hrs (which is a massive range) though the mean is around 30 hrs. There are a lot of issues with dosing in the early stages and can lead to significant accumulation and it has been noted in several papers that numerous death have occurred in the first week of methadone therapy.
- CYP3A4 inducers will increase methadone metabolism and reduced clinical effect
- eg carbamazepine, phenytoin and some anti-virals
- CYP3A4 inhibitors will reduce metabolism and increase clinical effect (where the real harm happens, either from resp depression or prolonged QT)
- these include fluconazole, a bunch of HIV drugs and erythromycin
Chronic Side Effects
- Prolonged QT
- a lot of people on methadone will have a prolonged QT. Like a lot of long QTs we find it’s likely meaningless. The risk probably comes with interactions with other drugs. If someone is on methadone and we add a drug that is also know to prolong the QT then there might be problems. Personally I doubt there’s an epidemic of torsades happening out there related to methadone and prolonged QT but it’s worth thinking about. [UPDATE ToxTalk thinks the QTc prolongation might be a real and important thing]
- the mechanism is related to hERG K+ channel. I know – that’s just changed your whole world right there hasn’t it?…
- as always with toxicology studies, it’s a mish mash of autopsy, animals and chart reviews. Not exactly the highest standard of evidence
- Methadone is commonly found in fatal ingestions and is most commonly found with benzos. Bottom line – benzos and methadone in an OD are a bad combo.
- Onset appears to usually be within the first few hours and one chart review found that everyone who got sick did so within the first 24 hrs
- as a result it has been frequently recommended to me that methadone ingestions warrant admission for at least 24 hr observation (ToxBase recommend this for all symptomatic patients) unlike standard heroin toxicity, where people are normally fit for discharge fairly quickly.
- the other recommendation is not to be too reassured by response to naloxone. Naloxone will indeed reverse some of the opioid effects, maybe just enough to allow them to abscond from the department just in time for the naloxone to wear off and the methadone to kick back in and they collapse and die in a corner. This happens. In general the best way to titrate your naloxone is breathing but still mainly unconscious.
- just like heroin, non-cardiogenic pulmonary oedema can occur
Comments or corrections welcome as ever.
Miscellaneous Methadone Facts James R Roberts Emergency Medicine News March 2009
Opioid Treatment of Opioid Addiction. McDonough, Michael. Australian Prescriber (June 2013): 1–5.
Lugo, Ralph, Kristin Satterfield, and Steven Kern. “Pharmacokinetics of Methadone.” Journal of Pain & Palliative Care Pharmacotherapy 19, no. 4 (January 6, 2005): 13–24. doi:10.1300/J354v19n04_05. PMID 16431829
Moody, David E. “Metabolic and Toxicological Considerations of the Opioid Replacement Therapy and Analgesic Drugs: Methadone and Buprenorphine.” Expert Opinion on Drug Metabolism & Toxicology 9, no. 6 (June 2013): 675–697. doi:10.1517/17425255.2013.783567. PMID 23537174 [WARNING - lots of complicated chemical structures and biochem in this one]
LoVecchio, Frank, Anthony Pizon, Brad Riley, Azadeh Sami, and Carmella D’Incognito. “Onset of Symptoms After Methadone Overdose.” The American Journal of Emergency Medicine 25, no. 1 (January 2007): 57–59. doi:10.1016/j.ajem.2006.07.006. PMID 17157684
Gruber, Valerie A, and Elinore F McCance-Katz. “Methadone, Buprenorphine, and Street Drug Interactions with Antiretroviral Medications..” Current HIV/AIDS Reports 7, no. 3 (August 2010): 152–160. doi:10.1007/s11904-010-0048-2. PMCID 2892618 [Open Access]
Methadone’s Cardiotoxicity. Notes from Dr RW
Journal Club Podcast #10: January 2014
Dr. David Newman-Toker, the authority on the HINTS exam, joins me to talk about oculomotor testing in acute vertigo...
Central Vertigo Video Links:
A HINTS exam consistent with vertigo of central should have at least one of the following: a normal head impulse test (without a corrective saccade), nystagmus that changes direction on eccentric gaze, or a positive test of skew deviation (vertical ocular misalignment).
Normal head impulse test
Positive test of skew
Peripheral Vertigo Video Links
A HINTS exam consistent with peripheral vertigo should have all of the following: an abnormal head impulse test (with a corrective saccade), nystagmus that does not change direction on eccentric gaze, and a negative test of skew deviation.
Abnormal head impulse test
Negative test of skew
Click Tab to ExpandArticles:
Article 1: Newman-Toker DE, Kerber KA, Hsieh YH, Pula JH, Omron R, Saber Tehrani AS, Mantokoudis G, Hanley DF, Zee DS, Kattah JC. HINTS Outperforms ABCD2 to Screen for Stroke in Acute Continuous Vertigo and Dizziness. Acad Emerg Med. 2013 Oct;20(10):986-996. Answer Key.
Article 2: Kattah JC, Talkad AV, Wang DZ, Hsieh YH, Newman-Toker DE. HINTS to diagnose stroke in the acute vestibular syndrome: three-step bedside oculomotor examination more sensitive than early MRI diffusion-weighted imaging. Stroke. 2009 Nov;40(11):3504-10. Answer Key.
Article 3: Newman-Toker DE, Kattah JC, Alvernia JE, Wang DZ. Normal head impulse test differentiates acute cerebellar strokes from vestibular neuritis. Neurology. 2008 Jun 10;70(24 Pt 2):2378-85. Answer Key.
Article 4: Newman-Toker DE, Saber Tehrani AS, Mantokoudis G, Pula JH, Guede CI, Kerber KA, Blitz A, Ying SH, Hsieh YH, Rothman RE, Hanley DF, Zee DS, Kattah JC. Quantitative video-oculography to help diagnose stroke in acute vertigo and dizziness: toward an ECG for the eyes. Stroke. 2013 Apr;44(4):1158-61. Answer Key.Vignette:
While moonlighting in a small, community hospital one evening, you are presented with a 58 year-old gentleman complaining of vertigo. He was at home eating dinner 5 hours prior to arrival when he felt the room begin to suddenly, and violently, spin around him. He notes “I haven’t felt like this since college!” He reports becoming nauseated and vomiting several times, then getting up and “staggering” to his bed where he laid down and tried to “wait it out.” After several hours of constant vertigo, he attempted to get up to go to the bathroom and fell to the floor. He managed to grab his cellphone and called 911. He reports the vertigo has been constant, is worse with any change in head position, and is associated with nausea and imbalance. He denies recent URI symptoms, hearing changes, focal weakness or numbness, or speech changes. His past medical history includes hypertension and diabetes, controlled with amlodipine, metformin, and glyburide. On exam, he has horizontal beating nystagmus. Cerebellar exam - including finger to nose, heel to shin, and rapid alternating movements - is otherwise normal. He has an abnormal Romberg’s and is unable to stand or ambulate unassisted. The remainder of his neurologic exam is normal. Head CT, ECG, and labs are all normal.
Your differential includes two main concerns: either the patient has vestibular neuritis and should be treated symptomatically and discharged, or he has suffered a cerebellar stroke and requires transfer to a hospital with neurology consultation and MRI available. When the patient does not improve after receiving oral meclezine and IV diazepam, you bite the bullet and transfer him to Barnes-Jewish for further evaluation by the stroke team. On your way home the next morning, you begin wondering if there are any aspects of the physical exam that can differentiate between peripheral and central causes of vertigo. A quick search of the literature identifies something referred to as the “HINTS” exam, which involves oculomotor testing. Specifically, this test includes evaluation of horizontal Head Impulse testing, the direction of Nystagmus, and Test of ocular Skew deviation. You begin delving deeper to determine if this is something you should be using in your practice…PICO Question:
Population: Adults with new-onset, acute vertigo with otherwise non-focal neurologic exam
Intervention: Bedside oculomotor testing (HINTS exam)
Comparison: MRI, discharge diagnosis, follow-up diagnosis
Outcome: Diagnostic accuracy, morbidity or mortality related to misdiagnosisSearch Strategy:
An advanced PubMed search was conducted using the terms "(HINTS OR oculomotor OR vestibuloocular) AND (vertigo or dizziness)," limited to humans and the English language, resulting in 142 citations (http://tinyurl.com/mktaevm). Original studies that reported sufficient data to construct 2X2 contingency tables were chosen for analysis. The bibliographies of relevant articles were searched for additional references. Three articles that specifically addressed the diagnostic accuracy of the HINTS exam were identified. An additional article was selected that assessed the 3 components of HINTS as well as vertical smooth pursuit, but allowed for calculation of the accuracy of the HINTS exam alone.Bottom Line:
Dizziness remains a common chief complaint in US emergency departments, leading to approximately 4 million visits every year (Saber Tehrani 2013). The emergency physician’s first duty in such cases is to distinguish benign peripheral causes of vertigo from more serious, potentially life-threatening, central causes. Making such a determination can be difficult: focal neurologic signs are absent in as many as 20% of cases of posterior circulation stroke (Tarnutzer 2011); computed tomography (CT) is frequently normal early in the course of posterior circulation stroke (Edlow 2008); and magnetic resonance imaging (MRI), often considered the reference standard for stroke, is associated with a significant number of false negatives when the posterior circulation is involved (Oppenheim 2000, Morita 2011).
Emergency physicians have identified the importance of a clinical decision rule to help differentiate central from peripheral etiologies of vertigo (Eagles 2008). The HINTS exam has been proposed as a means of making such a differentiation. This test involves 3 components:
1) Horizontal head impulse testing involves rapid head rotation by the examiner with the subject’s vision fixed on a nearby object (often the examiner’s nose). In cases of peripheral vertigo, a corrective saccade should be observed, and is considered a positive test. There is typically no corrective saccade in cases of central vertigo.
2) Evaluation of nystagmus will typically yield a fast phase which is unidirectional in peripheral vertigo, and beats away from the affected side. In central vertigo, the direction of the fast phase may change on eccentric gaze.
3) Alternate eye cover testing in patients with peripheral vertigo should result in no skew deviation or ocular tilt. Ocular misalignment and skew deviation (with or without ocular tilt) is frequently seen in patients with posterior fossa abnormalities (i.e. brainstem strokes).
While its individual components do not reliably differentiate central from peripheral causes of vertigo, an exam consisting of all three elements has been proposed to do so. In theory, if any of the components indicates a central pathology, then the exam is considered positive for a central etiology. All three components must be consistent with a peripheral etiology for the exam to be considered negative.
The current literature supporting the HINTS exam consists of four articles, three of which included patients from a single, ongoing prospective cross-sectional diagnostic study of patients with acute vestibular syndrome (AVS). The first article (Kattah 2009) included 101 patients with acute vertigo, of whom 76 were diagnosed with a central lesion. The diagnostic test characteristics of the HINTS exam for central vertigo were as follows: the sensitivity was 100% (95% CI 95.2-100.0), specificity was 96% (95% CI 79.6-99.3), likelihood ratio positive (LR+) was 25 (95% CI 3.66 to 170.59), and LR negative (LR-) was 0.00 (95% CI 0.00 to 0.11). Interestingly, the HINTS exam outperformed the initial MRI with diffusion-weighted imaging, which had a sensitivity for stroke of only 88%.
Similar diagnostic properties were identified in the 2nd paper (Newman-Toker 2013) which compared the accuracy of the HINTS exam to the ABCD2 score in 190 patients from the cross-sectional cohort. The ABCD2 score is a clinical prediction rule to predict short-term stroke risk following a transient ischemic attack. While this comparison seems contrived and unfair, the HINTS test performed quite well, with a sensitivity of 96.8% (95% CI 92.4-99), a specificity of 98.5% (95% CI 92.8-99.9), a LR+ of 63.9 (95% CI 9.13-446.85), and LR- of 0.03 (95% CI 0.01-0.09).
The 3rd study from this database (Newman-Toker 2013) used a small sample of 12 patients to evaluate the HINTS exam aided by a video-oculography device, which was used to record head and eye velocity measurements during head impulse testing. Physician interpretation of these reading was compared to an algorithmic interpretation, with 100% agreement. The aided HINTS exam demonstrated a high-degree of accuracy in the diagnosis of central vertigo, with a sensitivity and specificity of 100% (95% CI 54.1-100.0%), LR+ of ∞, and LR- of 0.
A 4th article was identified in which oculomotor testing was performed by neurologists, following completion of 4 hours of training specific to exam techniques and interpretation. Twenty-four patients admitted to the stroke unit were included in the study, of whom 10 were diagnosed with central vertigo. The sensitivity of the HINTS exam for stroke was 100% (95% CI 69.0 to 100.0), specificity was 85.7% (95% CI 57.2-97.8), LR+ was 7.0 (95% CI 1.9 to 25.3), and LR- was 0.
Several concerns were raised with regards to the current evidence. First, in these studies the HINTS exam was performed by specialists: neuro-ophthalmologists in two studies, neuro-otologists in one study, and neurologists with four hours of exam-specific training in the 4th study. This calls into question the external validity of the study, as the accuracy and reliability of HINTS testing in the hands of emergency physicians has not been evaluated. However, with some degree of training it is reasonable to expect emergency physicians to be able to perform the HINTS exam as proficiently as our specialist colleagues. When ED ultrasound was first being introduced, one of the primary concerns was that "only trained radiologists" could perform ultrasound and hence this was out of the jurisdiction of the ED. Over the years, we have not only proven capable of using ultrasound effectively in emergency medicine, but ultrasound is now a requirement of emergency medicine residency training. The question will be whether the amount of training necessary to become proficient with the HINTS exam will be worth the effort.
A second concern raised was that the patient populations in these studies were of moderate to high risk of central vertigo, with prevalence ranging from 42 to 75%. While the prevalence was high in all of these studies, these were still fairly heterogeneous groups of patients with variable risk (age ranges of 18-92, 26-92, 42-83, and 30-73) and hence did include some patients we would likely consider low risk. Some of the patients with stroke as the cause of symptoms were young (15 patients < 50 years of age in the study by Kattah et al). I would argue that some of these patients with central lesions would be treated as peripheral vertigo and discharged without advanced imaging at most institutions, and an abnormal bedside test would potentially lead to admission and further testing, and reduce the rate of missed stroke. In patients with low probability of disease, an abnormal HINTS exam may increase the pre-test probability of disease above the test threshold for MRI or admission. This is especially true at institutions without MRI or neurologic consultation available, where transfer to another hospital for admission and further work-up would be required to assess for a central etiology. In some moderate risk patients, a negative HINTS exam may reduce the probability of central etiology below the test threshold, and obviate the need for further work-up. For example, using the upper limits of the 95% CI for the negative LR from the largest study (Newman-Toker 2013) of 0.09, a patient with a pre-test probability of 25% for a central etiology who has a negative HINTS would have a post-test probability of 2.9%, and hence the decision may be made to not proceed with further work up.
Further testing of the HINTS exam will need identify a more concrete role for this test. The accuracy and reliability of the test in the hands of trained emergency physicians will need to be assessed, as will the impact of the test on both cost and patient care. If use of the test does not lead to either reduction in unnecessary imaging, reduction in the rates of missed posterior circulation infarction, or both, then it will not be worth the effort to train physicians in its performance. The role of the video-oculography device will also need to be further assessed in larger studies with more precise estimates of diagnostic accuracy to justify its cost.
This toxicology-themed Bud Light commercial was banned from airing during the 2007 Super Bowl.