Naltrexone plus Topiramate (in Rats)

Effects of naltrexone plus topiramate on ethanol self-administration and tyrosine hydroxylase gene expression changes.

Navarrete F, Rubio G, Manzanares J.

Addict Biol. 2013 Apr 9

I don't usually report animal research here but this study caught my attention.

Rats were given naltrexone (0.7 mg/kg) and/or topiramate (25 mg/kg). 

The authors note "naltrexone significantly reduced ethanol consumption and the motivation to drink during the different stages of the experiment, whereas the treatment with topiramate resulted in a much lower effect. Interestingly, the administration of naltrexone plus topiramate reduced ethanol consumption markedly compared with single-drug treatment".

I interpret this to mean that naltrexone helped some, topiramate just a little (sometimes statistically significant) but the combination was much better than naltrexone alone.

As both of these medications are used to help alcoholism in humans, it might be reasonable to add topiramate when a patient on naltrexone is not yet remaining sober (or vice versa). Epocrates does note an interaction between the two: "combo may increase risk of CNS depression, psychomotor impairment (additive effect)" although I could not find a PubMed reference.  Sedation can be a problem with topiramate. 

Using topiramate on top of naltrexone might require a more careful dose titration. Most studies of topiramate for alcohol dependence aimed for a dose of 300 mg daily, but this was limited by sedation. I found one open label study showing efficacy at lower dose of 75 mg daily.

Review by Jim Walsh, MD

Naltrexone to aid smoking cessation

Effects of the Opioid Receptor Antagonist Naltrexone on Smoking and Related Behaviors in Smokers Preparing to Quit: A Randomized Controlled Trial.
King A, Cao D, Zhang L, Rueger SY.
Addiction. 2013 May 28

Background:  Studies done looking at naltrexone for smoking have had mixed results, both positive and negative.  Limitations of prior studies include single dose naltrexone, inclusion of non treatment seekers and lack of long term follow-up (some studies looked at effects just hours after naltrexone).  Currently, the Cochran database states there is not enough evidence to make a recommendation either way.

Patient selection:  Patients had to be 18-65 years of age, smoke 12-40 cigarettes per day x2 years and had to report a desire to quit.  Study was also limited to patients with BMI between 19-38 and their liver function tests had to be < 2.5 times normal.  They could not be taking any opiate or other psychotropic medications, and could not have in the past year any major medical or psychiatric disorder.  They could not have any diagnosis of opiate abuse or dependence in their lifetime.  The study also declined patients who were pregnant or nursing.   Of the 707 individuals screened, 315 underwent randomization with a mean age of 42 years and 57% white.

Study design and methods:  The study was a double blind, placebo controlled, randomized study with randomization either to naltrexone or placebo.  There was a pre-quit phase, one week before the quit date, where patients randomized to naltrexone were given 12.5 mg on day 1, 25 mg on days 2 and 3, then 50 mg on day 4-7 (day 7 being the quit date).  After the quit date, both groups received weekly counseling sessions and nicotine patches (open label) for 1 month (post quit phase).  After the initial month, naltrexone or placebo was the only therapy.  Compliance was measured by urine, saliva and pill counts.  Participants filled out short questionnaires each night assessing number of cigarettes smoked, urge to smoke, smoking pleasure/taste, alcoholic drinks consumed, food/sweets consumption and caffeine intake (control).  Follow up was done as far out as 12 weeks (though this study is focused on correlation of pre-quit phase findings and post-quit results, not the results of naltrexone on tobacco cessation at 12 weeks.)

Results:   There was a 6% drop out rate, slightly higher in the placebo group, with "smoking related" causes being the most common.  Otherwise, naltrexone participants reported a higher incidence of nausea, dizziness and sedation (45% versus 22%) but this was rated as mild.  In the pre-quit phase, those with naltrexone had a 26% reduction in smoking (versus 17%, or, in terms of number smoked 4.21 fewer cigarettes per day versus 2.93 ), along with reduced smoking urge, cigarette taste and alcoholic consumption.  Other measures, when results were adjusted for demographics and nausea, were not significant (i.e. sweets consumption, food consumption/taste, smoking pleasure/taste).  When measured at one month, the naltrexone group continued to show reductions in cigarette number, reduced urge to smoke and alcohol consumption.  At 12 weeks, alcohol consumption remained reduced.

Moral of the story:  Naltrexone taken one week before a patient's quit date appears to reduce cigarette smoking, urge and alcohol consumption.

Thoughts:  Although the study included follow up at 12 weeks, the results of the 12 week follow up is detailed in a different study.  This study focused on whether data collected in the pre-quit phase could predict post-quit phase results.  

Review by Jacqueline Wong, MD. 

Steps Physicians Take to Reduce Diversion of Buprenorphine

Steps physicians report taking to reduce diversion of buprenorphine.
Yang A, Arfken CL, Johanson CE.
Am J Addict. 2013 May;22(3):184-7

This was a survey of over 2,000 buprenorphine waivered physicians.  Only 31% of those sent the survey completed it. Physicians were asked to select all steps they take to reduce inappropriate use or diversion of buprenorphine from a list of choices

Limit 30‐day prescriptions to complying patients	72.4%
Prescribe only the lowest effective daily dose	60.6%
Require regular urine screening or other drug screening	59.3%
Highly selective in accepting patients	47.1%
Coordinate services with counselors, pharmacists, and other physicians	46.5%
Require individual/group counseling unless not indicated	41.2%
Require more than monthly visits	34.2%
Random or frequent pill counts/medication recall	29.5%
At least one patient on greater than 16 mg of suboxone for maintenance	55.4%
Reassess patient when dose exceed 16 mg	24.6%
Ask family to observe pill taking	21.5%
Don’t use buprenorphine for maintenance	6.3%
Others	10.1%

Buprenorphine + Naloxone in Pregnancy

Buprenorphine + Naloxone in the Treatment of Opioid Dependence during Pregnancy-Initial Patient Care and Outcome Data.
Debelak K, Morrone WR, O'Grady KE, Jones HE.
Am J Addict. 2013 May;22(3):252-4

The authors report on 10 women treated with buprenorphine/nalolxone (Suboxone) rather than buprenorphine only (Subtex) in pregnancy.

Dosing was 8/2 up to 16/4 mg SL daily.  All urine drug tests negative at delivery.  This was not an especially high functioning or low risk group: none had completed education beyond high school (six had a high school degree), all but one had never married, none were employed full‐time, and one was currently involved with the criminal justice system.

There were two maternal medical complications: one case of pre‐eclampsia and one oligohydramnios. There was one c-section.

Neonates were, generally speaking, full‐term infants with normal birth parameters. One baby was born premature after PPROM, leading to an average gestational age 37.5w and average birth weight 6lbs 3 oz.

Four neonates were treated for NAS, needing on average 3.5 mg morphine over 6.9 treatment days.

The authors conclude: Findings do not raise obvious concerns for clinicians who might be considering treatment of opioid‐dependent pregnant women with buprenorphine þ naloxone.  They did note the need for further research

Prazosin for Alcohol Dependence

Thanks to Dr. Saxon for sharing this article at the 2013 Fundamentals of Addiction Medicine Conference

A Pilot Trial of the Alpha-1 Adrenergic Antagonist, Prazosin, for Alcohol Dependence.
Simpson, T. L., Saxon, A. J., Meredith, C. W., Malte, C. A., McBride, B., Ferguson, L. C., Gross, C. A., Hart, K. L. and Raskind, M. (2009), Alcoholism: Clinical and Experimental Research, 33: 255–26

The authors had noted reports of decreased alcohol use when prazosin as used for the treatment of PTSD, prompting this pilot study.

24 patients were enrolled (out of 120 screened) and randomized to placebo vs prazosin.
A lot of patients were excluded.  The reasons for not being enrolled were:

not interested once learned what was involved, including not willing to be abstinent (n=37)
current PTSD or other psychiatric condition requiring medication other than an anti-depressant (n=28)
in other treatment or in controlled living environment (n=21)
no drinking past month or no AD (n=12)
scheduling difficulties or no reliable way to contact (n=11)
medical contraindications or already taking prazosin (n=6)
currently using opiates (n=>4)
outside of age range (n=>1)

The prazosin was given at a fairly high dose, 4 mg AM, 4 mg PM and 8 mg HS. They note that all the patients but one was able to titrate up to the full dose. They started at 1 mg HS for the first two days and titrated up to the full dose over two weeks. Patients were seen twice weekly the first two weeks then weekly thereafter.

The medication was well tolerated. Systolic BP decreased 6.6 mm Hg on average and diastolic decreased 3.3 mm Hg. No patient had orthostatic hypotension. 4 patients dropped out, none related to medical effects. The prazosin group reporting taking 92% of their study medication doses, the placebo group 87%.

Patients had brief medical management counseling visits, similar to the COMBINE trial.

Baseline alcohol use was not the most severe. In the 42 days prior to the study there were about 28 drinking days, 20 heavy drinking days and 4-5 drinks per day.

The data analysis is somewhat complex. There was no differences over the 6 weeks in mean drinks per week or mean drinking days per week, although both groups decreased use 2.78 drinks per week.

 If the first 3 weeks are excluded, as the medication was still being titrated up, there were fewer drinking days per week in the prazosin patients than the placebo group (β = −1.22; 95% CI = −2.29 to −0.14; p = 0.027). The average total number of drinking days was 5.9 for the placebo group, and only 3.2 for the prazosin group. There was no difference between the groups in mean drinks per week during those final 3 weeks.

Data was reanalyzed looking just at the male subjects as only three women completed the trial and only one woman was in the control group.  Looking at the just the 17 male study completers (7 prazosin and 10 placebo) efficacy appeared quite impressive.  6 of the 7 prazosin men were abstinent at study completion vs 4 of 10 placebo men.   The placebo men drank on average 20.8 total drinks over the last 3 trial weeks vs 2.6 for the prazosin men.  The placebo men had on average 5.7 and the prazosin men 0.9 drinking days over those 3 weeks.

The authors noted they did not see a decrease in craving for alcohol in the prazosin (vs placebo) patients even as used decreased.

This small pilot study demonstrates a new possible medication option for treatment of alcohol dependence. The authors explain a plausible mechanism or prazosin to decrease alcohol relapse.  The data for the men only subgroup shows impressive efficacy although the larger analysis did not.

With this degree of evidence, I think it would be reasonable to offer prazosin to help male patients reduce drinking if there is also some evidence of PTSD.  I look forward to larger study of prazosin.  The major change in my practice will be to move doses to the higher range demonstrated in this study.  

Focal nonconvulsive seizures during detoxification for benzodiazepine abuse

Focal nonconvulsive seizures during detoxification for benzodiazepine abuse.
Epilepsy Behav. 2012 Feb;23(2):168-70
Albiero A, Brigo F, Faccini M, Casari R, Quaglio G, Storti M, Fiaschi A, Bongiovanni LG, Lugoboni F.
Department of Medicine D, Addiction Unit, University of Verona, Verona, Italy.

The authors report on two cases focal seizure activity that occurred during flumazenil treatment of benzodiazepine withdrawal.  Low-dose flumazenil was given by IV infusion (0.5 mg/day) for 14 hours daily over 10 days, with discontinuation during the night. On the same day of admission, the abused BDZ was replaced with clonazepam, which was progressively tapered over the next 3 days, so that on 4th day the patient was no longer receiving BDZs. 


The episodes were confirmed by EEG. One is described as 

On the 8th day she suddenly developed behavioral changes characterized by impairment of consciousness (the patient was able to perform simple tasks such as open her eyes), sometimes with upper limb automatisms, lasting several minutes and alternating with long periods of normal behavior. No posturing, rotation, or clonic movements occurred. There were no secondarily generalized tonic–clonic seizures. 

And for the other patient:

On the 9th day she suddenly developed behavioral changes characterized by clusters of episodes with confusion, disorientation, fear, and partial impairment of consciousness (the patient was able to perform only simple tasks), lasting several minutes and alternating with periods of normal behavior. No limb or oroalimentary automatisms, posturing, rotation, or clonic movements were observed. There were no secondarily generalized tonic–clonic seizures. 

The first patient was on Depakote at a dose of 500 mg BID with a level of 54 mg/L.  Episodes continued until least day 11 when EKG changes were demonstrated.  The patient was changed to carbamazepine and discharged at the high dose of 400 mg TID.

The second patient was on oxcarbazepine (Trileptal) at 600 mg/day when the episodes began.  Her episodes recurred days 12, 13, 14, 15.  One the 15th day EEG changes were noted during an episode. Her oxcarbazepine was increased to 900 mg/day.

The authors note a 2.8% incidence of generalized seizures among the 286 patients they have treated with flumazenil. The article implies an anticonvulsant was used in these patients generally but does not specify which one, what dose or serum levels.

What should we conclude from this?  Localized seizures can occur during benzodiazepine withdrawal just at generalized seizures do.  That is the significant new finding.

The presence of one of these episodes with a valproic acid level of 54 contradicts our experience that seizures don't occur when therapeutic levels of valproate are present.  It is possible that this assumption incorrect but also possible that the level of 54 mg/L was inadequate to prevent seizures.

I have seen one patient with focal seizure activity that progressed over several hours to a generalized tonic clonic seizure.  This patient had sub-therapeutic carbamazepine  hen the episode occurred. They did not recur when carbamazepine was dosed adequately. 

Predictors of death for methadone maintenance patients in Croatia

Croat Med J. 2013 Feb 15;54(1):42-8.

Risk factors for fatal outcome in patients with opioid dependence treated with methadone in a family medicine setting in Croatia.

Cerovecki V, Tiljak H, Ozvacic Adzic Z, Krizmaric M, Pregelj P, Kastelic A.

The authors report on 287 patients treated with methadone maintenance by Croatian family doctors between 1995 and 2007.  It unclear to what extent doses were observed.  They note 16.7% self-administered methadone, 9.8% were administered methadone by someone else, 73.5% used "a combined model".

During the 12 years 8% or 23 patients died for an annual mortality of 0.7%.  The greatest risk factor was previous failure of methadone treatment Odds Ratio 19, loss of continuity of care OR 12, unstable family relationships OR 9, an intention for maintenance vs detox (presumably reflecting a more chronic opiate addiction) OR 3 

It wasn't stated but implied that overdose is the cause of much of this mortality.  The maximum dose allowed in this setting was 50 mg methadone daily and it appears that patients likely to use additional substances or to take methadone erratically were at the highest risk of death.

This may not apply in the US context where methadone doses are higher and daily observed dosing is the norm, but it suggests that previous failures at methadone maintenance or unstable family relationships may be an indication for more careful monitoring.