"Whoever saves a life, it is considered as if he saved an entire world."
Mishnah Sanhedrin 4:5; Yerushalmi Talmud 4:9, Babylonian Talmud Sanhedrin 37
Mishnah Sanhedrin 4:5; Yerushalmi Talmud 4:9, Babylonian Talmud Sanhedrin 37
I have a patient on alprazolam, and need to taper her off. What’s the best way to do this?
There are two great resources for guiding benzodiazepine tapers – the Ashton Protocol and the Canadian Guidelines.
The Ashton Protocol allows patients to follow the protocol with you each week and uses the self-tapering properties of diazepam (note – nordiazepam (=desmethyldiazepam) has a half-life of up to 200 hours, which makes it awesome for gently tapering benzodiazepines and allowing the body to readapt/naturally renew its own GABAergic activity as exogenous benzodiazepine levels gradually drop). I would not recommend the Ashton protocol for elderly patients with significant medical co-morbidities because the extended half-life of diazepam is not forgiving if you overshoot in the conversion process.
Another awesome and simpler resource is the Canadian Guidelines. I adapted this for use in Monterey County and have created a smartphrase hyperlink below to it:
What if I need to get someone off of a benzodiazepine fast (e.g. a patient would like to start treatment with buprenorphine but the clinic won’t allow co-prescription of a benzodiazepine)?
Most rapid benzodiazepine tapers don’t work well and confer a high risk of relapse.
Although there are data to support relatively rapid (weeks rather months) benzodiazepine tapers using valproic acid, gabapentin, carbamazepine, and pregabalin, the best way to do a rapid (3 days), effective, and safe benzodiazepine taper is with phenobarbital in an inpatient setting. Hyperlink to a great article on the Hopkins phenobarbital protocol here.
What’s the best way to taper venlafaxine (Effexor) or paroxetine (Paxil) (two agents notorious for producing severe, serotonergic withdrawal)?
SLOWLY and using a fluoxetine bridge.
Don’t rush the taper for either of these agents e.g. dropping a dose of paroxetine 40 mg daily by 10 mg per week would be reasonable. When you get to the lower doses of paroxetine and venlafaxine, and you are getting close to discontinuation, add fluoxetine 10 to 20 mg daily x 3 days to create your fluoxetine bridge, and then discontinue. The fluoxetine, with its active metabolite, norfluoxetine, which has a half-life of 4 to 16 days, will stabilize the serotonin system; and the long half-life ensures a gradual decrease in serotonergic transmission, which allows your body to compensate naturally (adaptive upregulation of serotonergic transmission) + avoid withdrawal.
For psychopharmacology geeks only:) - Why does paroxetine produce such a bad withdrawal syndrome even with a couple missed doses?
Paroxetine is a potent Cytochrome P450 2D6 and 3A4 inhibitor, and, therefore, inhibits its own metabolism. When paroxetine levels in the body decrease, either with missed doses or a taper, inhibition of paroxetine’s metabolism also decreases, resulting in a surge of rapid self-metabolism.
This double hit may account for the severity of the withdrawal phenomena: hit 1 = the dropping levels of paroxetine; and hit 2 = the increase in paroxetine's metabolism by hepatic isoenzymes, which had previously been inhibited by paroxetine but are now liberated/disinhibited because of the lower paroxetine plasma levels (Drug-Drug Interaction Primer, Neil B. Sandson).
How do you optimize the treatment of OCD for a patient already on clomipramine and with failed trials of SSRIs?
a) In addition to the atypical antipsychotics and benzodiazepines, there are increasing data to support the effectiveness of glutamatergic medications (N-acetylcysteine (NAC), memantine, lamotrigine, topiramate) as augmenting agents for OCD (Laoutidis et al., J Clin Psych, 2016). For the patient we saw in clinic this week, we chose to use NAC because of its benign side effect profile and ease of use (no titration schedule/can be started at a therapeutic dose).
Hyperlink to NAC Review article describing its multifarious, pharmacodynamics properties (= glutamatergic, antioxidant, and anti-inflammatory) and emerging treatment data across diverse psychiatric disorders here.
Hyperlink to randomized controlled trial of NAC for OCD here.
b) ALSO, there are data to support the combination of low dose fluvoxamine and clomipramine for treating refractory OCD (Szegedi et al., J Clin Psychiatry, 1996). Here, you are not using fluvoxamine as an augmenting agent not for its pharmacodynamic properties, but rather you are tapping into its pharmacokinetic effects as a pan-inhibitor of the hepatic isoenzymes responsible for metabolizing clomipramine to desmethylclomipramine.
Clomipramine (CMI) has greater serotonergic potency and purported therapeutic efficacy than desmethylclomipramine (DCMI). Desmethylclomipramine has more adverse side effects than clomipramine. Therefore, this combination increases the ratio of clomipramine’s therapeutic (clomipramine) to adverse (desmethylclomipramine) effects through a controlled drug-drug interaction.
Here are recommendations for how to titrate this combination from Ivan Goldberg, a true master of clinical psychopharmacology (now deceased):
Days AM PM
1-10 fluvoxamine 50 mg clomipramine 50 mg
11-20 fluvoxamine 100 mg clomipramine 100 mg
21 and after fluvoxamine 150 mg clomipramine 150 mg
(Source: Goldberg, Email Communication, 2011)
Note: this combination requires obtaining serial plasma levels during titration to determine the ratio of CMI to DCMI; you should also monitor LFTs. From the 1996 study referenced above, “Clinically relevant side effects were absent in patients with serum CMI and DCMI levels below 450 ng/mL and ratios of N-demethylation below 0.3.”
Why should you consider vortioxetine for a patient with unipolar depression who has significant cognitive symptoms/dysfunction?
Vortioxetine is a potent SSRI, which also acts as a 5-HT 1A and 1B receptor partial agonist and as a 5-HT3 and 5-HT7 receptor antagonist. In three randomized controlled trials designed to test its effects on cognition (Katona et al., 2012; Mahableshwarkar et al., 2015; McIntyre et al., 2014), patients taking vortioxetine compared to the placebo group demonstrated modest but clinically meaningful improvements (with a Cohen’s d effect size ranging from 0.25 to 0.48) in attention, memory, learning, processing speed and executive function; these pro-cognitive effects were independent of improvement in depression.
Based on the CONNECT trial (Mahableshwarkar et al., 2015), in which vortioxetine separated from both duloxetine and placebo in improving cognition, it has received approval in Europe as an agent specific for enhancing cognitive function in patients with depression. It may receive similar approval in the U.S., pending further FDA review.
Your patient with a history of alcohol use disorder, in early remission, and chronic, unipolar depression, presents with insomnia. He has failed trials of sleep hygiene and trazodone. You think the insomnia may be a residual symptom of his depression or a manifestation of prolonged, subsyndromal alcohol withdrawal. Why would gabapentin be potentially useful for this patient?
In addition to harnessing the sedative effects of gabapentin dosed at night, gabapentin has data to support its use for multiple phases in the treatment of alcohol use disorder.
a) Gabapentin for relapse prevention and reduction in drinking:
I have a smartphrase below for how to use gabapentin to prevent relapse and/or reduce drinking from an excellent study conducted by Mason et al. + published in JAMA in 2014. This was a 12-week double-blind randomized placebo-controlled trial (DBRCT), with 150 treatment-seeking alcoholics, abstinent x 3 days or greater. The investigators found clinically significant reductions in relapse (number needed to treat (NNT) of 8), heavy drinking (NNT of 5), and severity of craving, insomnia, and dysphoria in the gabapentin arm compared to placebo. Greatest efficacy was achieved in the 1800 mg subgroup.
Smartphrase, .RxGabaEtoh, to get:
Day 1: 300 mg at bedtime
Day 2: 300 mg in the morning and at bedtime
Day 3: 300 mg three times daily
Day 4: 600 mg at bedtime; 300 mg in the morning and in the afternoon Day 5: 600 mg in the morning and at bedtime; 300 mg in the afternoon Day 6: 600 mg three times daily
Source: Mason et al: Gabapentin Treatment for Alcohol Dependence: A Randomized Controlled Trial. JAMA Intern Med. 2014 January 1; 174(1): 70–77.
Other supporting data from Furieri et al., 2007; Brower et al., 2008; Anton et al., 2011. b)
b) Gabapentin in combination with naltrexone for early reduction in drinking:
A study published by Anton et al. in American Journal of Psychiatry in 2012 tested a cool, biologically and clinically driven hypothesis that many naltrexone non-responders may suffer from protracted withdrawal symptoms, such as sleep disruption and affective instability, which are not effectively targeted by naltrexone’s antagonism of mu opioid receptors (best behaviorally correlated with reductions in craving). The investigators, therefore, tested gabapentin (titrated to 1200 mg per day) as an add-on treatment to naltrexone during the first 6 weeks of treatment following detox, and found that the gabapentin + naltrexone group beat the naltrexone + placebo group on clinically significant outcomes including total alcohol use, time to heavy drinking, and number of heavy drinking. These differences then faded after gabapentin was discontinued in weeks 7 through 16.
In addition to the Anton study above, three other studies (Bisaga, 2006; Myrick, 2007; Karam-Hage, 2003) have demonstrated that gabapentin can be safely used for alcoholics, who are actively drinking or relapse. Unlike benzodiazepines, gabapentin had no adverse effects on respiratory drive; in one of the studies (Bisaga, 2006), gabapentin did worsen balance compared to alcohol alone but did not produce excess sedation or synergistic cognitive impairment.
c) Gabapentin for Detoxification:
Multiple studies now support the use of gabapentin rather than a benzodiazepine (Watson, 1997; Myrick, 1998; Vorick, 2003; Myrick, 2009; Stock, 2013) or phenobarbital (Mariani, 2006) to treat withdrawal in patients with no history of complicated withdrawal and without significant risk factors for complicated withdrawal. Additionally, these studies suggest that patients prescribed gabapentin rather than a benzodiazepine have a reduced likelihood of relapse.
There are also several negative studies (Bonnet, 2003; Bonnet, 2010) in which gabapentin has not shown efficacy for treating alcohol withdrawal. In one of these studies (Bonnet, 2010), two patients in the gabapentin arm experienced withdrawal seizures. However, this study was open-label, and it selected inpatients who had severe rather than mild to moderate alcohol withdrawal symptoms. The other negative study above by Bonnet (Bonnet, 2003) compared gabapentin + a benzodiazepine to placebo + a benzodiazepine in the treatment of alcohol withdrawal; although gabapentin failed to separate from placebo, the design of this study was fundamentally flawed. It does not ask or answer the question – should gabapentin be used instead of a benzodiazepine for treating alcohol withdrawal; and, given the immediate anxiolytic and potentially euphoric subjective effects of a benzodiazepine, it likely biased participants against both placebo and gabapentin add-on.
Clinical Summary: I think there are sufficient data to support the preferential use of gabapentin rather than a benzodiazepine for detoxification in patients, who have mild to moderate withdrawal symptoms and who do not have a history of complicated withdrawal or other risk factors for complicated withdrawal. These patients should be reliable participants in their own treatment, meaning they can be trusted to go to the ED if more acute withdrawal symptoms emerge. I would also consider using gabapentin rather than a benzodiazepine in patients seeking to detox from alcohol who are abusing other substances, such as opioids, which could have dangerous interactions with benzodiazepines.
By using the smartphrase, .rxgabadetox, you can autopopulate the gabapentin detox protocol below:
1. Gabapentin 400 mg three times daily for 3 days
2. Then gabapentin 400 mg in the morning and at bedtime on day 4
3. Okay to use additional 300 mg dose of gabapentin x 1 on day 1 for breakthrough symptoms of withdrawal
4. Okay to use additional 100 mg dose of gabapentin x 1 on days 2 through 4 for breakthrough symptoms of withdrawal
5. Thaimine 100 mg daily for 12 days
Reference: Myrick H, Malcolm R, Randall PK, Boyle E, Anton RF, Becker HC, Randall CL: A double-blind trial of gabapentin versus lorazepam in the treatment of alcohol withdrawal. Alcohol Clin Exp Res. 2009 Sep;33(9):1582-8.
*Other supporting data from Watson et al., 1997; Myrick et al., 1998; Voris et al., 2003; Mariani et al., 2006; Stock et al., 2013.
d) Prominent sleep disruption in patients recovering from alcohol use disorder:
A study by Bazil et al. (2005) tested the effects of gabapentin in combination with alcohol on sleep. The investigators took healthy subjects, got them drunk before bed;), and then compared sleep with gabapentin (600 mg) versus placebo. They found that gabapentin quelled the rebound hyperarousal that disrupts sleep after drinking + increased slow wave sleep, sleep efficiency, and decreased time spent in phase 1 sleep, REM, and nocturnal awakenings.
Clinical Summary: gabapentin may be useful for treating insomnia characterized by multiple night awakenings, decreased sleep efficiency and the problems with sleep often seen in recovering alcoholics. Similar results have been found in active drinkers with insomnia (Mason et al., 2009; Karam-Hage et al, 2000; Brower et al., 2008).