Naltrexone vs Suboxone, a longer study

The Lancet just published a study (X:BOT) comparing extended-release naltrexone (XR-NTX) with buprenorphine/naloxone (BUP-NX) for opioid relapse prevention, this one with 6 months of follow-up, showing similar safety and efficacy of the 2 therapies (see doi.org/10.1016/S0140-6736(17)32812-X). Study sponsored by National Institute on Drug Abuse. [i appreciate and have incorporated the inputs from Ian Huntington and Joe Wright]

 

Details:

--570 people from 8 US community-based programs

--70% male, mean age 34,75% white/18% Latino/10% African-American, 63% unemployed

--64% injection drug use, primary opioid in prior 7 days: 80% heroin/16% opioid analgesics (prescription pills)/2% buprenorphine/1% methadone, age of onset of opioid 21 yo,duration of use 9 yrs, 50% also on stimulants/30% sedatives/25% heavy alcohol/45% cannabis, 68% psychiatric disorder, 7% depressed. 

--most had low-severity opioid use (they did not define this, other than to say that high-severity use was at least 6 bags or equivalent of intravenous heroin per day in the 7 days prior to admission)

--participants : >18 yo, DSM-5 defined opioid use disorder, and had used nonprescription opioids in past 30 days. 

--exclusions: if other serious medical, psychiatric or substance use disorders; transaminases >5x upper limit of normal; suicidal or homicidal; had methadone maintenance treatment (>30mg/d); or had chronic pain requiring opioids.

--detox protocols varied by site

--those on XR-NTX​ went through acute inpatient detox, were at least 3 days from last opioid use, had negative opioid urine, and negative naloxone challenge (no or minimal withdrawal symptoms after naloxone)

--those on BUP-NX had observed dosing in the detox unit and were seen frequently, at least weekly initially, about 11 visits

--median maintenance bup dose was 16mg/d

 

Results:

--XR-NTX had significant induction hurdle (as expected, see below): only 72% of 283 patients successfully initiated XR-NTX vs 94% of 287 pts with BUP-NX 

--intention-to-treat analysis: relapse events at 24 weeks: 65% with XR-NTX vs 57% for BUP-NX: HR 1.36 (1.10-1.68)

--BUT, most or all of this difference in relapse rates was accounted for by the induction failures of XR-NTX 

--similarly for opioid-negative urine samples and opioid-abstinent days: big difference in intention-to-treat analysis, but none in those who had successful induction

--no difference in treatment effects by sex

--opioid craving was initially less with XR-NTX than with BUP-NX, but was no different by week 24. With both drugs, opioid craving decreased dramatically in the first 2 weeks,more gradually til week 8, then basically plateaued

--retention rates at 24 weeks was similar (and not so great) in both groups by those who succeeded in induction: 47% in the 204 patients in XR-NTX and 43% in the 270 patients in BUP-NX

--adverse events: only difference was injections site reactions in the XR-NTX group.  and, notably, no difference in fatal overdoses (2 with XR-NTX, 3 with BUP-NX), and, if looking only at those who made it through the induction phase (ie, were actually on the XR-NTX), there were 9 people on XR-NTX and 7 on BUP-NX​ who had one or more ODs, with the total number of ODs being 10 vs 9.

Commentary:

--so, this study does add a lot to the prior one, which did not have long enough followup(see http://gmodestmedblogs.blogspot.com/2017/10/extended-release-naltrexone-vs.html). these are the only 2 head-to-head comparison studies

--XR-NTX is a sustained opioid receptor blocker, so requires full detox prior to starting (hence the issue above with non-initiators). BUP-NX​ can be initiated safely in an outpatient setting in those in mild-to-moderate withdrawal

--One small study (see Mannelli P. Drug Alc Depend 2014; 138: 83) used low doses of buprenorphine and oral naltrexone in a more opioid dependent population (75% had severe opioid dependence of > 6 bags/d and 25% with moderate of 3-6 bags/d of heroin). in this study, 20 patients were in a 7-day outpatient XR-NTX induction involving decreasing doses over 3 days of buprenorphine starting at 4mg, and increasing doses over 7 days of naltrexone starting at 0.25 mg.  Fifteen of the 20 (75%) successfully concluded the induction phase (similar%  to above, but in a more opioid-dependent population). Might be worth repeating this type of study but with more patients and different cities/centers, especially if XR-NTX is to become a real alternative for patients, since ease of detox is a significant limitation to XR-NTX. Still, one pretty large advantage of BUP-NX is that the whole process can be done quite easily in the outpatient setting.

--One major concern with XR-NTX​, as noted by Joe Wright after the first study blog, is that these patients may well develop decreased opioid tolerance (upgrading of their downgraded mu-receptors), and if they go back to using street drugs, may overdose by taking their old dose, as has been seen in people getting out of jail. There was a systematic review (see Sordo, L. BMJ 2017; 357:j1550) finding that methadone patients had 3.2 times the all-causemortality when stopping methadone therapy and 2.2 times the mortality in those stopping suboxone, noting that the "time immediately after leaving treatment with both drugs are periods of particularly increased mortality risk" [though, this is observational study and those stopping treatment may be fundamentally different from those who continued, and not fully accounted for by their multivariate adjustment].  And a longer trial of 153 community-dwelling people on XR-NTX found that up to 78 weeks later there were no overdoses at all in the XR-NTX ​group (see Lee JD. N Engl J Med 2016; 374:1232). These studies are somewhat reassuring about the risk of ODs with XR-NTX, but we should remain vigilant.

--in my somewhat limited experience, it is really common with BUP-NX to have patients continue to “relapse” (ie, have opiates in their urine) for some time after starting the BUP-NX. Sometimes this is for a few weeks, sometimes for many months, and this is why we see patients every week initially and until they are stable on the med and off opiates (and several patients co-using heroin with their BUP-NX​ for many months do eventually stop, perhaps with a few blips). This would be a big difference between XR-NTX and BUP-NX, since the BUP-NX allows for this more gradual transition off the opiates, which many patients seem to need. The above study's  curve of "time to relapse" was steepest in the first 4 weeks, then plateauing at around 16 weeks, which is consistent with what i have found. But this raises the issue of whether we should be considering all the people who used opiates early as failures. seems like the wrong outcome: would be better to look both at those who stopped using opiates consistently at perhaps the 3-month mark, as well as those who significantly decreased their opiate use (harm reduction, which i think is still beneficial for the patient/less reliance on street drugs and their unknown contaminants like fentanyl)

--and, these studies do raise the other addiction issues: 25% heavy drinkers, very likely very high percentage smokers (not mentioned in either this or the prior naltrexone blog, but in my experience is really high), etc. as mentioned in prior blog (see http://gmodestmedblogs.blogspot.com/2017/10/smoking-in-hiv-patients-and-focusing-on.html​ ​, which talks about smoking in HIV patients, 40% of whom smoke), it is really important that we clinicians (and patients) continually address these other harmful behaviors and not just have quick check-ins on how the opiate addiction is going.

so, some more data suggesting that opiate use disorder can be treated with injectable extended-release naltrexone. the big caveat is that it is likely useful for a limited number of patients: those not only highly motivated but also willing to go through a complete/thorough detox beforehand. and many patients are not able to do so, for a variety of reasons. one political concern in this regard is that the current US president/appointees, in their general punitive/vindictive/'moralistic" approach, are against buprenorphine since it is "treating an opioid addiction with another opioid", an approach which (as with others) flies in the face of science and reality.