The Abuse Potential of Gabapentinoids

I first started prescribing gabapentin in the 1990s, as part of an early attempt to see if it worked for bipolar disorder.  It was an off-label approach and did not have that indication.  At the time anticonvulsant approaches to bipolar disorder (valproate, carbamazepine) were being heavily used.  I was following a number of people who could not take lithium and on anticonvulsants and they seemed to do surprisingly well.  Gabapentin seemed to have significant advantages in terms of toxicity, it was well  tolerated by most people.  Unfortunately, it was completely ineffective for bipolar disorder and I stopped trying it almost immediately.

The next off label application that surfaced was for chronic pain.  Any psychiatrist is exposed to a number of patients with chronic pain or chronic pain and addictions, and it became apparent that it was being used successfully for chronic back pain, chronic headaches, and post herpetic neuralgia.  Over the next decade, gabapentin and then pregabalin was prescribed for chronic pain indications and people seemed to do reasonably well with it - even at relatively high doses.

At some point, physicians working in detox and the addiction field started to use gabapentinoids for chronic pain, anxiety, and withdrawal.  It is not uncommon to see patient with all of these problems who is not able to tolerate antidepressants for those symptoms or who needs more immediate relief.  In fact, in residential addiction treatment it is common to see patients come in on high doses of gabapentin for chronic back pain.   They are there for treatment of an opioid use disorder, but during that time have not escalated the gabapentin dose.

In the literature reports of gabapentin misuse have been surfacing over the past 5 years (1-7).  A large review (4) suggests that 1.3% of the treated population is at risk for gabapentinoid misuse with the number being much higher is some populations such as opioid users.  There is a report (3) that patients with opioid use disorder will attempt to augment the eurphorigenic effect of methadone in a similar way that they use benzodiazepines.  Benzodiazepine use with methadone in methadone maintenance clinics is a chronic and at times lethal problem.  There is a report from Norway (5) that gabapentinoids may be useful is reducing benzodiazepine use.  The report generally suggests that the abuse potential is low and greater for pregabalin than gabapentin.  There is an insurance database report (6) that looks at an overuse metric comparing gabapentinoids to other abused drugs.  Goodman and Brett (7) comment on the epidemiology of gabapentinoid prescribing, specifically an increase in gabapentin prescriptions from 39 million in 2012 to 64 million in 2016 with an associated doubling in the sales of pregabalin during the same period.  They attribute the increase to attempts to treat chronic pain without opioids in primary care, suboptimal non-opioid medications (acetaminophen and NSAIDs). They cite mixed evidence in clinical trials, side effects, misuse or diversion, and an excessive focus on pharmacological measures for pain as being concerns.       

Are there biases in these report?  There certainly are.  I don't have access to the full text of the most comprehensive paper (2), but I would be interested in looking at the actual numerator and denominator for their numbers and how much was based on actual pharmacovigiliance/pharmacosurveillance as opposed to case reports, case series and reports of complications.  The other issue is that all of these papers seem to come from the same publisher.  I have not encountered that before.

The only study that I could find that looked at the direct question of concomitant use of opioids and gabapentin came from Canada (8).  It studies a large group of patients on a database that records the prescriptions and looked at all opioid users that died of opioid related causes between 1997 - 2013.  The big picture is that there were a total of 2,914,971 opioid users during the study time frame and 6,745 died of opioid related causes.  Then by selection criteria they identified 1,256 cases and matched them to 4,619 controls. They defined gabapentin exposure as concomitant gabapentin use in the 120 days preceding the index date.  They also looked for a dose response relationship of gabapentin doses considered as low (<900 mg daily), moderate (900 to 1,799 mg daily), or high (≥1,800 mg daily).  They also did a comparison with nonsteroidal anti-inflammatory drugs (NSAIDs) used as an adjunctive pain medication instead of gabapentin.  Their results are summarized in the following tables excerpted directly from the article (click to enlarge):

 
As noted from the data and analysis, 12.3% of the controls and 6.8% of the cases were prescribed gabapentin in the 120 days, representing a 50% increased risk of death in the gabapentin treated cases.  In the case/control comparison both groups have roughly the same levels of mental illness but the case group had higher utilization of antidepressants (all types), benzodiazepines, and other drugs/CNS depressants. They were also taking substantially more high dose opioid therapy (>200 MME).  Higher dose gabapentin nearly doubled the risk. There was no added effect from NSAID use.  The authors conclude that caution needs to be exercised in deciding to prescribe this combination (opioids + gabapentin) and that if that decision is made it needs to be carefully monitored.  From my perspective I had some concerns about the controlling for benzodiazepine use in the case/control comparison and did not see any risk attributable to benzodiazepines.  The authors do cite a reference that led to FDA warnings about the benzodiazepine-opioid combination. 

Given the concerns about gabapentin why use it at all?  The main reason is that it is effective for some of the most difficult problems in medicine.  It is very difficult to see people with extreme anxiety and insomnia go for weeks without sleep and experience continuous panic attacks all day long.  When a person stops taking benzodiazepines that they have been taking for years that is a frequent result.  The same is true for people who have decided to stop drinking and suddenly have very high levels of anxiety and insomnia now that their baseline anxiety is back.  More to the point, unless something can be done to provide them with timely relief, relapse to drug and alcohol use is certain.  Finally does high levels of abuse by some patients with addictions suggest that the medication is unsafe?  It is probably safer then other medications in this population and extremely safe outside of those populations.  In either case safety depends on whether there is a physician involved or the medication is acquired from nonmedical sources.   

Standard practice with gabapentin should be to tell all patients (in addition to the usual discussion and detailed information) the following information.  I point out here that I do not prescribe pregabalin:

1.  Take this medication exactly as it is prescribed.
2.  Do not accelerate the dose of the medication.
3.  Do not mix this drug with alcohol or any other intoxicants or street drugs.  If a relapse occurs call to discuss and set up a plan as soon as possible.
4.  Do not stop the medication abruptly it needs to be slowly tapered.  There is a seizure risk if it is not.
5.  This medication is potentially addictive to some people. If you notice any tendency to take more of this medication than prescribed contact me immediately.
6.  This medication is monitored on the state Prescription Monitoring Program and all prescriptions are recorded even though it is not technically a scheduled drug at this time.

At least that is the way that I think it should be handled.  If I was still seeing a lot of patients with chronic pain on moderate to high doses of opioids I would add in a line or two about the the Canadian study (9) and greater chances of death from the gabapentin + opioid combination.  In my current practice, psychiatric treatment is split off from buprenorphine detox and maintenance treatment - but I still see a lot of patients on buprenorphine + gabapentin and can attest to the fact that in a controlled environment we have not observed the complications suggested by the Canadian study over a period of months.  None of these patients receive benzodiazepines or sedative hypnotics beyond a period of detox.  In fact, doing that study might be a significant contribution to the research.  It also probably means that those patients when they are discharged should hear that the risk of taking that combination may increase substantially in the outpatient setting.

There is plenty of politics and confusion surrounding the gabapentinoids issue.  It should not be surprising that this medication is showing up in the toxicology of opioid overdose victims. It should not be surprising that some people try to get "high" on it, even though the people doing that do not have typical ideas about the utility of medications. It should not be surprising that people try to use gabapentin like benzodiazepines to augment the effect of what they are using to get high especially opioids.  It should not be surprising that when some people decide to stop buprenorphine or methadone that they will buy somebody's gabapentin to try to treat withdrawal effects.  It should not be surprising that in some areas it is currency on the street (What can I get for a month's worth of gabapentin?).  It should not be surprising that it has become a political football in the social media on pain ("See it's not opioids as the problem - it is gabapentin") or the social media on weed ("See these are Big Pharma solutions, marijuana is much safer").  It should not be surprising that you can read about it on drug culture web sites where everyone is an expert pharmacologist and provides you with anonymous advice on how to get high. It should not be surprising that you can buy it online and have it delivered to your door, although you can never really be certain that it is the same stuff you get at Walgreens.  I am always amazed at how easy it is to sell some Americans drugs, if they think there is the slightest possible chance they can get high on it. That is also why it should not be surprising that children and teens will take it out of medicine cabinets - use it to get high and brag about it even though there were probably not high at all.

The features about the gabapentinoids that make sense to me is that they are medically useful  and have low toxicity, for people with nearly impossible problems in desperate situations.  It is a less toxic drug on the street than those mentioned in the above paragraph. Even then these drugs need to be carefully prescribed and closely monitored.  And even then some people will escalate the dose. There are no perfect solutions in medicine and in this area in particular - nothing seems to be coming down the pike.  The probability statement is always - does the use of gabapentin result in more people with improved symptoms, better quality of life and less addiction?  At this time unless presented with compelling evidence I would say that it does with the qualifier that its application needs to be carefully done by a physician who knows what they are doing and is aware of the potential for misuse. In  the current era, that can all be subject to the next social media fad.

There is not a big push by the pharmaceutical industry at this time to discover a drug that has limited toxicity that can be used for severe chronic pain, insomnia, and anxiety associated with addictive disorders.  There is also the question of what medications are being used for these problems if not gabapentin.  The answer is atypical antipsychotics (mostly quetiapine), hydroxyzine (a first generation antihistamine), and clonidine (primary use is hypertension and opioid withdrawal).  If the comprehensive toxicology of overdoses is available I would expect to see these compounds listed.  In any search of drug interactions both quetiapine and hydroxyzine are flagged as potentially affecting cardiac conduction. Clonidine can cause hypotension if used excessively and rebound sympathetic symptoms (tachycardia, hypertension, diaphoresis).  Looking at that group of medications gabapentin would appear to have the preferred side effect profile.

There also appears to be a big push to make gabapentin a controlled substance according to the Controlled Substances Act (CSA).  Pregabalin is currently a Schedule V drug (see page 14) or considered to have the lowest abuse liability.  Getting on that list depends on how the DEA currently sees the addictive behavior towards gabapentin versus pregabalin.  Putting a drug on Schedule V will probably have no impact on how it is used in medical practice or out on the street.  The fact that pregabalin is ranked so lowly is a sign of regulatory opinion on abuse liability.

That's my current opinion on the topic.  I may add more to this post in the future or to a post I am working on about the basic science of gabapentinoids.


George Dawson, MD, DFAPA


References:

1:  Schifano F. Misuse and abuse of pregabalin and gabapentin: cause for concern? CNS Drugs. 2014 Jun;28(6):491-6. doi: 10.1007/s40263-014-0164-4. Review. PubMed PMID: 24760436.

2:  Chiappini S, Schifano F. A Decade of Gabapentinoid Misuse: An Analysis of the European Medicines Agency's 'Suspected Adverse Drug Reactions' Database. CNS Drugs. 2016 Jul;30(7):647-54. doi: 10.1007/s40263-016-0359-y. PubMed PMID:27312320.

3:  Baird CR, Fox P, Colvin LA. Gabapentinoid abuse in order to potentiate the effect of methadone: a survey among substance misusers. Eur Addict Res. 2014;20(3):115-8. doi: 10.1159/000355268. Epub 2013 Oct 31. PubMed PMID: 24192603.

4:  Evoy KE, Morrison MD, Saklad SR. Abuse and Misuse of Pregabalin and Gabapentin. Drugs. 2017 Mar;77(4):403-426. doi: 10.1007/s40265-017-0700-x. Review. PubMed PMID: 28144823.

5: Smith, R. V., Havens, J. R., and Walsh, S. L. (2016) Gabapentin misuse, abuse and diversion: a systematic review. Addiction, 111: 1160–1174. doi: 10.1111/add.13324.

6: Bramness JG, Sandvik P, Engeland A, Skurtveit S. Does Pregabalin (Lyrica(®) ) help patients reduce their use of benzodiazepines? A comparison with gabapentin using the Norwegian Prescription Database. Basic Clin Pharmacol Toxicol. 2010 Nov;107(5):883-6. doi: 10.1111/j.1742-7843.2010.00590.x. PubMed PMID: 22545971.

7: Peckham AM, Fairman KA, Sclar DA. Prevalence of Gabapentin Abuse: Comparison with Agents with Known Abuse Potential in a Commercially Insured US Population. Clin Drug Investig. 2017 Aug;37(8):763-773. doi: 10.1007/s40261-017-0530-3. PubMed PMID: 28451875.

8: Goodman CW, Brett AS. Gabapentin and Pregabalin for Pain - Is Increased Prescribing a Cause for Concern? N Engl J Med. 2017 Aug 3;377(5):411-414. doi: 10.1056/NEJMp1704633. PubMed PMID: 28767350.

9: Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink W.  Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study. PLoS Med. 2017 Oct 3;14(10):e1002396. doi: 10.1371/journal.pmed.1002396. eCollection 2017 Oct. PubMed PMID: 28972983; PubMed Central PMCID: PMC5626029.

Graphics Credit:


Figure 2 about is excerpted directly from the work in reference 8 above per the Creative Commons Attribution License.  The authors are listed as the copyright holders.


Supplementary:

Publication from the above content?  If you are a psychiatrist or pharmacologist and think you can rework the above article into a publication.  Contact me and let's write that paper!