With all the quotes in the media about these withdrawal
syndromes – I thought I would add a few facts.
These facts are based on science, my 22 years in acute care psychiatry,
and another decade at a large facility specializing in substance use disorders.
I have been involved in the care of thousands
of people with these disorders, and the care has improved substantially over
that period of time largely due to the availability of Medications for Opioid
Use Disorder (MOUD). Before that there
was a major problem treating anyone with an Opioid Use Disorder (OUD) if they
were not enrolled in a methadone maintenance program.
To cite a few examples, in acute care psychiatry it is
common to receive emergency admissions of people with severe depression or
psychosis. Many have associated drug and
alcohol problems. In the case of heroin
and other opioids, there was a rule extending up into the early 2000s that
unless a person was enrolled in a methadone maintenance program, only acute
detox could be done with methadone.
Additional medications were offered like clonidine to cover
hyperadrenergic symptoms of opioid withdrawal.
Clonidine was often the only detox medication. The situation was not
better in substance use disorder (SUD) treatment programs who often had an
array of “comfort medications” designed to treat all of the peripheral symptoms
of withdrawal. The problem with this
approach was twofold: first it was rarely adequate to treat acute withdrawal. Second,
when the patient was discharged in a week, they had ongoing symptoms of
withdrawal that essentially guaranteed an immediate relapse to opioid use.
The introduction of buprenorphine (Suboxone, Subutex,
Sublocade) resulted in a marked improvement in the quality of care in this
scenario. The acute and chronic withdrawal symptoms of opioids could be
adequately treated and the risk of relapse mitigated. During the time of this
transition, the large SUD treatment center where I was working went from using
buprenorphine for acute detox to buprenorphine maintenance treatment. I was responsible for treating depression and
anxiety in these patients. I observed
that no matter what treatment I prescribed the anxiety, insomnia, irritability,
and depression persisted for months as protracted opioid withdrawal symptoms until
they were treated with buprenorphine. At
that point the withdrawal symptoms resolved immediately and completely. The depression, anxiety, insomnia, and craving
for opioids all resolved. That massive
improvement in care cannot be emphasized enough. I went from discharging people after 1-3
months who I knew would relapse immediately to confidently discharging people
who were stable and had a much better chance to recover.
I am posting this introduction because the historical window
for this innovation was very brief and I doubt that many physicians ever saw
it. The advantage for patients was so
clear that the medical director of the treatment program where I worked changed
it from an abstinence-based program to MOUD. The research at the time was clear. MOUD saved lives by decreasing relapse rates,
accidental overdoses, and decreased risk of infections (HIV, HCV).
In my previous post, I examined the rhetoric of comparing
selective serotonin reuptake inhibitor (SSRI) withdrawal to heroin
withdrawal. But what about the popular
myths and the science? The popular view
of opioid withdrawal is that once the acute phase is over – it is over. The popular view promoted with SSRI
withdrawal is that it is typically universal, severe, and long lasting. Neither of those views are accurate.
The time course of symptoms is outlined in the diagram at
the top of this post. Acute symptoms
have a characteristic pattern and can start as soon as hours after a last dose
of heroin. In the case of
antidepressants, the time course is more dependent on the mechanism of action
and half-life of the medication being studied. Since opioids are all mu opioid
receptor (MOR) agonists – there are no known medications in this class that do
not cause withdrawal, but what accounts for the differences in severity and
percentages of people affected is not known. Pharmacokinetics and
pharmacodynamics likely play a role – I will defer that discussion to later
post.
The main qualitative differences in opioid and SSRI withdrawal are the lack of cravings and observable physical symptoms in SSRI withdrawal. Opioids reinforce their own use and for that reason have street values. SSRIs do not and have no street value. The withdrawal symptoms from SSRIs are largely subjective but that does not mean they are not real or serious.
In the case of SSRIs and other antidepressants, the
mechanism precipitating withdrawal is thought to be a precipitous fall in
extraneuronal serotonin. All SSRIs are
orthosteric inhibitors of the serotonin transport protein (SERT). Orthosteric inhibitors act like serotonin at
the same binding site on SERT. Allosteric
modulators bind at a site that is topographically distinct from the site that
the endogenous ligand (in this case serotonin or 5-HT) binds to. Escitalopram has an additional effect on SERT
as an allosteric modulator. Trazodone,
vilazodone, and nefazodone are all allosteric non-competitive inhibitors of
SERT (1-4). Withdrawal reaction have
been described by both but not to the same degree as heroin withdrawal.
In the case of heroin withdrawal, a series of studies done from 1962 to 1969 showed very high relapse rates (>90%) in heroin users who had been treated in a controlled environment. Thise studies led to early experiments with MOUD and eventually methadone maintenance. A direct comparison of the likelihood of moderate withdrawal symptoms for each category is 3-31% for SSRIs and 100% for opioids. Those numbers are qualified by several caveats. First, opioid withdrawal has been studied for a much longer time, is more well characterized, and fewer medications are involved. Second, study methodology for the SSRI withdrawal is much more varied from looking at short term randomized controlled studies to surveys of long-term use selected for withdrawal symptoms. The former will underestimate withdrawal effects but identify a drug attributable effect by subtracting out placebo and the latter will overestimate effects . The overestimate can be compounded by not subtracting a nocebo effect and publicity effects that may increase nocebo. In clinical practice, using antidepressants with lower withdrawal risk – I found the incidence to be closest to that of Henzler, et al (7) at about one in six or seven people.
In conclusion, discontinuing many medications can cause a withdrawal syndrome. Not all withdrawal syndromes indicate an addiction and some can be life-threatening. They are difficult to study for several reasons. First, the response to discontinuing the medication varies significantly from person to person even at the same dose and duration of use. That range is significant from no effect to severe and in some cases (alcohol, sedative hypnotics) life-threatening effects. That includes a placebo response where that can be safely implemented. Second, there is also a lack of high-quality evidence for many of these syndromes. The best evidence is for alcohol and sedative hypnotics because they are obvious and have been treated for decades. But even then there are consensus guidelines such as the ASAM guideline on benzodiazepine tapering. Third, there is limited standardization across guidelines. Fourth, there are pharmaceutical limitations. In some cases, very small doses of medication are needed to complete the protocol that may require a liquid form, pill cutting, or substitution with an equivalent medication with a longer half-life. In some cases, all of these changes may not be enough. Fifth, in clinical trials where medications were tapered and discontinued there may not be enough reported details to replicate the protocol in clinical practice (5). Sixth, the outcomes of discontinuation of a medication are complex and include resolution of adverse drug effects, relapse to the treated condition, a unique withdrawal syndrome, or a rebound effect involving the physiological systems that were being treated – like rebound tachycardia after stopping beta-blockers. Seventh, context is important especially with medications and substances that reinforce their own use. Adherence to any tapering protocol on an outpatient basis is much less likely to happen. Eighth, the medicolegal dimension may be a concern. Because of the all of these factors, there is a lot of uncertainty involved in any tapering and discontinuation protocol. There is seldom a protocol that will work well for everyone. Because of this risk some guidelines advise clinicians to seek legal or administrative consultation when attempting these protocols. There is additional risk if relapse to the original condition occurs after a medication has been successfully stopped.
Despite all these concerns tapering and discontinuing
medications is foundational medicine in any medical specialty. None of these
problems are unique to psychiatry or medication for mental disorders. As interns most physicians learning how to
detoxify acute care patients with substance use disorders – the most common
condition remains alcohol use disorder.
In their respective specialties – they learn more about how to do this
with specific medications used in their specialty. That has resulted in
protocols that can differ from hospital to hospital in the same town. In some cases,
the protocols differ in the same hospital over a period of years. To cite one example, I am aware of a hospital
that used oxazepam followed by diazepam and then chlordiazepoxide or phenobarbital
as their detox agents from alcohol and benzodiazepines. In some of the standard
orders, anticonvulsants were also used to minimize seizure risk.
As more societies and government agencies get involved there
is a gradual move to standardization. Even if we get to that point – individual
assessments and close monitoring will still need to be done. The risk of a withdrawal syndrome from any
medication is one that is necessary to medically treat various problems. It is a decision that physicians and patients
do not take lightly. It is important to
discuss that potential risk in the informed consent discussion.
George Dawson, MD, DFAPA
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