Acute Pregabalin Withdrawal: A Case Report and Review of the Literature

Jaclyn A. Barrett, PharmD

Lindsay M. Kittler, PharmD, BCPS

Clement Singarajah, MD, FCCP

Phoenix VA Medical Center

Phoenix, AZ 85012

Abstract

Objective: Pregabalin is a commonly prescribed GABA analog most commonly used for the treatment of neuralgia. Recently, case reports on pregabalin have been published describing episodes that may be associated with withdrawal-like symptoms after extended or aggressive therapy. This report describes a case in which long term exposure of high dose pregabalin may have resulted in acute withdrawal, and outlines the subsequent medical management of these symptoms.

Case Summary: A 61-year-old male presenting with severe agitation presumed to be withdrawal from long term and high dose exposure to pregabalin. Medical management included the use of haloperidol, diphenhydramine, lorazepam and the addition of clonidine over the course of several days for the pharmacological management of withdrawal symptoms.

Discussion: Although case reports are available to guide clinicians in the recognition of acute pregabalin withdrawal, definitive evidence on how best to treat these patients remains severely limited. With an increase in the prescribing practices of pregabalin, insight into the acute management by fellow clinicians is further needed.

Conclusion: Caution must be practiced when prescribing and educating patients on the use of pregabalin to prevent associated withdrawal-like symptoms. In addition, documentation by the medical community on methods utilized to treat pregabalin withdrawal syndromes remains crucial for the advancement of patient care. Benzodiazepines and clonidine are the current therapies that have been documented as potentially effective treatment modalities at this time.

Introduction

Pregabalin is a gamma-aminobutyric acid (GABA) analogue currently FDA labeled for diabetic peripheral neuropathy, fibromyalgia, neuropathic pain, partial seizures and postherpetic neuralgia, and is used off-label in various psychiatric disorders. It is proposed that pregabalin binds strongly to an alpha-2-delta subunit on voltage gated calcium channels within the central nervous system. Pro-nociceptive neurotransmitter release that is dependent upon calcium is thereby reduced. Additional mechanisms for pregabalin’s efficacy may be comprised of noradrenergic and serotonergic pathways involved in pain transmission (1).

Case Presentation

We report the case of a 61-year-old man who presented with sudden and severe withdrawal like symptoms characterized by family as extreme agitation with combative behavior, diaphoresis, tachycardia, hypertension, tremors, and incontinent diarrhea. Reportedly, prior to admission, the patient had become increasingly somnolent with multiple falls and psychotic behavior similar to one responding to internal stimuli. A review of his home prescription vials revealed a presumed, excessive consumption of immediate-release oxycodone and pregabalin over the last few days and up to a week. His past medical history included chronic obstructive pulmonary disease, osteoarthritis, neuropathic pain, hypothyroidism, hyperlipidemia, anxiety and major depressive disorder. A thyroid stimulating hormone level was checked upon admission and was within normal limits with no other metabolic explanation for his symptoms identified. The patient did present with a prior medical history of opioid abuse with previous enrollments in substance abuse programs, but compliance with his current pain management contract was confirmed using the state’s controlled substance prescription monitoring program database.

Upon admission through the emergency room, the patient remained severely agitated with increasingly combative behavior despite the administration of the antipsychotic, haloperidol. Without relief, the benzodiazepine, lorazepam, was administered resulting in a paradoxical effect causing increased aggression and agitation and thus discontinued. Implementation of scheduled hydromorphone was administered for acute opioid withdrawal but similarly provided minimal symptom abatement yet, maintained adequate analgesia. After medication review and reconciliation, the patient was currently on a prescribed, scheduled dose of pregabalin 300 mg twice daily over the course of approximately eight months for the treatment of neuropathic pain. Although initially concerned for potential overdose, all symptoms upon presentation were deemed to be consistent with a withdrawal syndrome, pregabalin being the most likely culprit given lack of symptom abatement with the use of benzodiazepines and opioids with no other likely cause upon review of his home medications and laboratory data.

After transferring to the Intensive Care Unit, the patient was further treated with intravenous haloperidol 10 mg and diphenhydramine 50 mg every 4 hours providing only minimal relief while protecting both the safety of the patient and staff. Management of acute pregabalin withdrawal was further complicated by the inability to provide pregabalin orally, due to disorientation and the physical inability to maintain placement of a nasogastric tube. Sedation and mechanical ventilation was not an option as the patient’s established wishes were a Do Not Intubate (DNI) status. Sublingual clonidine 0.1 mg was later administered every four hours and up to every hour if needed, in addition to the haloperidol and diphenhydramine. The anti-adrenergic agent clonidine was most effective in providing withdrawal symptom reduction, and the haloperidol and diphenhydramine were rapidly tapered off. In addition, our patient developed urinary retention necessitating the discontinuation of diphenhydramine. The discontinuation of diphenhydramine lead to a retrial of lorazepam which provided effective relief for the management of his later course agitation with no paradoxical agitation observed.

This case demonstrates an issue of common occurrence, where a patient is withdrawing clinically from a drug with often non-specific symptom manifestations. Further confounding this clinical presentation, several possible sources of drug withdrawal required the medical team to address each drug individually in order to identify the offending agent. With this in mind, withdrawal from pregabalin, although not often considered a drug of abuse or associated with intense withdrawal, may only be identified by ruling out other suspected agents, such as in this patient scenario.

Discussion

In review of current literature, case reports have arisen that describe symptoms of withdrawal from abrupt discontinuation of pregabalin. Several case reports describe a withdrawal-like syndrome to include signs and symptoms such as agitation, anxiety, confusion, gastrointestinal distress, tachycardia and palpitations, similar to benzodiazepine withdrawal (2-4).

Oaklander and Buchbinder (2) report a case involving an 80-year-old woman prescribed pregabalin 125 mg three times daily for 49 weeks as treatment for postherpetic neuralgia. Within 36 hours of abrupt discontinuation, the patient developed severe nausea, headache, imbalance, delirium and anorexia. Over the course of several weeks, the patient developed hemodynamic instability and continued to experience episodes of ataxia for a six month duration.

Another report by Karosin et al. (3), describes a 47-year-old male who reportedly consumed a total daily dose of 7,500 mg of pregabalin daily in addition to alcohol and cocaine abuse. In a failed attempt to wean off pregabalin the patient developed what was described to be vegetative withdrawal symptoms, sweating, restlessness, hypertension, tremor and pregabalin cravings. Upon admission, the patient received treatment with benzodiazepines without relief and a slow taper of pregabalin was initiated yet, cravings continued which ultimately resulted in the patients continued abuse of this GABA analog.

In a case report by Norgaard et al. (4), a 38 year-old man was self-administering 8.4 g pregabalin daily and within 36 hours of cessation of pregabalin developed auditory hallucinations and suicidal ideation in addition to sweating, anxiety and tachycardia. Pregabalin was reinitiated at 600 mg per day in addition to supplemental chlordiazepoxide and quetiapine. Acute symptoms resolved within 48 hours yet the symptoms of psychosis remained present until several weeks after discontinuation.

In addition, case reports regarding gabapentin withdrawal have been published to include similar clinical presentations. Gabapentin, another GABA analog, is FDA approved for the treatment epilepsy, neuralgia and restless leg syndrome, and is widely used in the prophylaxis of migraines, headaches and ethanol withdrawal (5). It is hypothesized that the mechanism of withdrawal is associated with increased activity of the enzyme responsible for producing GABA, similar to the mechanism behind ethanol and benzodiazepine withdrawal (6).

Hellwig et al. (6) and Mah et al. (7), describe similar symptoms of irritability, confusion and agitation unrelieved by the administration of benzodiazepines. Gabapentin was identified as the causative agent of withdrawal after reinstatement of the GABA analog provided relief in both case reports. In addition to drug related factors, potential patient related risk factors that may increase the susceptibility of withdrawal include advanced age and history of psychiatric illness.

Currently, pregabalin is a schedule V controlled substance due to its potential for addiction and abuse (8). According to the manufacturer, there are no current recommendations for the management of an acute drug withdrawal syndrome from pregabalin, yet current practice suggests that a gradual taper, generally recommended with all extended controlled substance therapy, may be warranted. This report suggests that clonidine may be an effective agent in the management of acute agitation associated with pregabalin withdrawal. Literature has historically supported the use of clonidine in a variety of drug withdrawal syndromes owing to its known central alpha 2 agonist activity, but remains underutilized amongst providers in current practice (9-11). Another alternative to consider is dexmedetomidine, a centrally acting, alpha 2 adrenoceptor agonist which has demonstrated its efficacy as an adjunctive treatment for refractory alcohol withdrawal (12). Due to concomitant hypertension and institutional cost, dexmedetomidine was considered second line in the event that clonidine was ineffective for our patient.

Although case reports are available to guide clinicians in the recognition of acute pregabalin withdrawal, definitive evidence on how best to treat these patients remains severely limited. With an increase in the prescribing practices of pregabalin, insight into the acute management by fellow clinicians is further needed to provide evidence-based guidance in the management of these patients. As for our clinical case of acute pregabalin withdrawal in the presence of hallucinatory features, we advise against the use of benzodiazepines due to the risks of paradoxical agitation, and would suggest withholding their use until the latter stages of withdrawal. If possible, as was not in our case, initiating a pregabalin taper would ideally preferred. We also propose that the use of clonidine has clinically shown, as demonstrated in this patient case, to provide appropriate supportive treatment for the management of acute pregabalin withdrawal.

References

1. Pregabalin. DrugPoint Summary. Micromedex. Truven Health Analytics, Inc. Greenwood Village, CO. Available at: http://www.micromedexsolutions.com. Accessed April 26, 2014.
2. Oaklander AL, Buchbinder BR. Pregabalin-withdrawal encephalopathy and splenial edema: a link to high-altitude sickness? Ann Neurol. 2005;58(2):309-12. [CrossRef] [PubMed]
3. Karosin C, Kofler M, Mayr A, et al: Pregabalin: A treatment option for dystonia? Neurol Sci. 2012;33(2):351-4. [CrossRef] [PubMed]
4. Nordgaard J, Jurgens G. A case of pregabalin abuse. Clin Toxicol. 2013;51(4):320
5. Gold Standard, Inc. Gabapentin. Clinical Pharmacology [database online]. Available at: http://www.clinicalpharmacology-ip.com/Forms/drugoptions.aspx?cpnum=271&n=Gabapentin&t=0 Accessed: 5/19/2015.
6. Hellwig TR, Hammerquist R, Termaat J. Withdrawal symptoms after gabapentin discontinuation. Am J Health Syst Pharm. 2010;67:910-2. [CrossRef] [PubMed]
7. Mah L, Hart M. Gabapentin withdrawal: case report in an older adult and review of the literature. J Am Geriatr Soc. 2013;61(9):1635-7. [CrossRef] [PubMed]
8. LYRICA® (pregabalin) CV Safety Info. Available at: http://www.lyrica.com. Accessed April 27, 2014.
9. Baumgartner GR, Rowen RC. Clonidine vs chlordiazepoxide in the management of acute alcohol withdrawal syndrome. Arch Intern Med. 1987;147:1223-6. [CrossRef] [PubMed]
10. Baumgartner GR, Rown RC. Transdermal clonidine versus chlordiazepoxide in alcohol withdrawal: a randomized, controlled clinical trial. South Med J. 1991;84:312-21. [CrossRef] [PubMed]
11. Robinson BJ, Robinson GM, Mailing TJB, Johnson RH. Is clonidine useful in the treatment of alcohol withdrawal? Alcohol Clin Exp Res. 1989;13:95-8. [CrossRef] [PubMed]
12. Tolonen J, Rossinen J, Alho H, Harjola VP. Dexmedetomidine in addition to benzodiazepine-based sedation in patients with alcohol withdrawal delirium. Eur J Emerg Med. 2013;20:425. [CrossRef] [PubMed]

Reference as: Barrett JA, Kittler LM, Singarajah C. Acute pregabalin withdrawal: a case report and review of the literature. Southwest J Pulm Crit Care. 2015;10(5):306-10. doi: http://dx.doi.org/10.13175/swjpcc059-15. PDF

Comments

[Josh]

I've heard nothing good about this drug. It's absolutely terrifying. Thank you for writing it all out so I could see how devastating it was without actually trying it.

[Deb.50@live.co.uk]

I am scared to death and wanting to withdrawal from this horrid drug pregabalin . I take 150mg twice daily, I ran out and went two days without pregabalin and had horrific withdrawal first constantly sweating from my head /face like a tap was on my forehead and agitation like no other, I could not sit still, lie down ..I cudnt stop moving! it was horrid and my body was shaking and buzzing uncontrollable! it was hell..! Please any help to get me off these would be greatly appreciated, I've read clonidine can help! Thankyou deb

[Lynn]

Deb,
I was put on Lyrica several years ago after major back surgery to repair a pinched nerve. The nerve pain after surgery was unbearable and left me incapacitated. Lyrica has been a lifesaver for me... allowing me to have a normal life again. I was taking 175 mg 3X a day. About 6 months ago I started reducing the dosage to see if the pain had decreased. Slowly I have lowered my dosage and now I am only taking 75 mg 3X a week! I have noticed 3 side-effects: 1) Sweating (mostly at night), 2) Minor irritability, 3) Weight loss. My plan is to continue lowering the dosage until I am completely off. Lyrica may not be for everyone but it made my life much better when I needed it. Take is slow and don’t distress—Lynn (with a new life)

[Dave]

This is one very terrifying drug! Please take it exceptionally slow when tapering or the horrors of hell will be all yours

[bev.]

I am in the process of coming off Lyrica, stepping down from 450 mg daily and I am now at 31 mg in the morning and 25 mg 12 hours later. What I have learned 1) the drug has been sold as safe and just may not be so very safe. 2) it lasts 12 hours in our bodies for taking it only once a day, or every other day means we are in withdrawal after 12 hours, needless torcher. 3) I have learned how to dissolve the powder into hotish water to step down at a very slow rate to avoid the side effects of withdrawal. Here is how. mg = ml. So I empty a 75 mg capsule into a glass and add 75 ml of hat water, still and the place into containers. 31 mg x 2 containers and throw the remainder away. Before I drink I add a bit of juice to avoid the taste.
I guess the most important is slow and every 12 hours. People survive from the hellish drug.

[Cath O'Connor]

I was on Lyrica 150mg twice a day for nerve pain. After 10 months with not a lot of relief I tried cupuncture and lo and behold after 4 treatment NO MORE neerve pain. I waited untl I had been nerve pain free for 3 months and then consulted gp about stopping lyirica. I obeyed directions 150mg and 75mg for a week 75mg x 2 for a fortnigh 75mg a day for a week then stop. Midway through the week of 75mg per day I began night sweats, anxety attacks, itchy eyes, nose and skin, diaorhea and irritability. I had no idea it was withdrawal from lyrica. Went to gp who said 'classic withdrawl symptoms'. and I went back to 75mg twice a day for 6 days and a further weel if no tich, then 75mg a day for 10 days before stopping. HOwever this time the itch, sweats etc began on the first day on no Lyrica. Now I am on a third try to get of them. This time 50mg once each day for a fortnight then 25mg once each day for a fortnight. Fingers crossed folks.

[jhall9765@gmail.com]

iabruptly ended taking lyrica 400 mgs a day, after three years use, cold turkey. in two days chronic vommitting, sweats, headaches agitation,. hands and feet were on fire, i lasted a week like this before getting back on lyrica 400 mgs. it was hell on earth.

[Cath O'Connor]

Following from above. On my third attempt to wean off pregalbin, I took it in three stages of 14 days each and eventually it was ok. Although I often have the dry eyes and sweats but nowhere near as bad. Wouldn't recommend this drug to anyone.

[Jackie]

I was on pregablin for 3 years taking 300mg twice a day. Weaned off of them over 2 months. I had all the symptom everyone else has had, nearly drove my insane. I have been off of pregablin for 1 month now my symptoms have nearly all gone apart from not sleeping and weakness and overall pain. I was on pregablin for anxiety.

[Jackie]

I was on pregablin for 3 years taking 300mg twice a day. Weaned off of them over 2 months. I had all the symptom everyone else has had, nearly drove my insane. I have been off of pregablin for 1 month now my symptoms have nearly all gone apart from not sleeping and weakness and overall pain. I was on pregablin for anxiety.

[Pete]

I ve been on and off Pregabalin for aprox 3 yrs now. I always manage to quit for a few months, but then I crave it again. I use it for GAD - general anxiety disorder. 150mg per day. But I must admit I am very irregular in taking it. Sometimes I took triple the daily dose, sometimes I skipped a day or few. I always stopped using it very abruptly - and hell yes I experienced all sorts of things. One time it was actually amazing, I had so much energy even though I slept like 3hours a day, I managed to go for a run, swim and be productive for 10days straight. Then, I just physically collapsed. But...I could go without it for few months again. Another time, I broke my leg and it is not advised to take Lyrica when you are in the process of healing bone fractures, because it messes up calcium metabolism somehow. I could go without Lyrica for 4months straight...I made a huge mistake by "trying to just take the last 5 pills I had left" and now I crave it again:(
It helps me a lot for managing my anxiety, but it has severe adverse effects on me. I wish I could live without it or I wish there is alternative.

[Sam]

Here’s a fun fact: I got hooked on lyrica because I was traveling and ran out of Xanax - for me, it did a marvellous job of substituting for benzodiazepines and was over the counter in that country. When I got back to the US, my doctor was delighted to prescribe it for me indefinitely so that I did not go back to abusing benzos.

It is 3 years later and I wish I’d stuck with the benzos! Because, while lyrica will treat benzo withdrawal - benzos will NOT help with lyrica withdrawal. As this article points out. So instead of being able to do a slow and cheap diazepam taper, I’m stuck taking this super expensive and equally addictive substance with a short half life that requires extreme discipline to get off.

I finally got sick of being dependent on pharmaceuticals and went to Peru to do a traditional detox involving frog poison. Don’t laugh, it got me off long term suboxone and Adderall with a single treatment. But within 24 hours I was on a bus to Cusco to buy more lyrica... even this super detox didn’t help the lyrica withdrawal in the slightest.

This shit needs to be pulled from the market.

[Tracy Campbell]

I have been taking pregabalin for years 150mg twice a day for chronic pain. A few times I've been unable to refill due to forgetting about bank holidays or travelling longer than anticipated. I have terrifying withdrawals which start only 3 hours after a missed dose. Sweating, burning up, chills, shivers, vomiting, diarrhoea, panic attacks. I'm very scared about stopping, scared to keep taking. My doctors and pharmacist don't think I should be having any withdrawals, even though they know to taper. Scary!

[Joe Goldston]

I was prescribed Lyrica 150 mg tid for panic attacks while getting off Suboxone for a Restless Legs Syndrome. I had fatigue and nausea when I tried to go from 75 mg twice a day to none and I made it 5 days before the agitation and suicidal ideation got the best of me. I was able to”break” the attack by taking 225 mg over several hours. I have tried to stop twice more and am now on 25 mg every other day and I have been able to control the suicidal ideation and panic with Vistaril 25 mg. I have taken it three times during a day but that has been effective at this lower dosage level so far. I hope to keep tapering and finally be off but it sounds like that could be months from the time of cessation.

[Mia]

Resperidone works well for acute withdrawal symptoms

[Carl]

I’m in the middle of weaning off 300mg twice a day. This is a medication that can help people who suffer from chronic pain. When you are prescribed the paperwork clearly explains that there will be a trade off concerning some symptoms but you have to decide if the payoff is worth it. I guess it’s not meant for people who just may heal. I’ve been very Ill for over a week. Im glad to know it’s the Lyrica. At least this is temporary. Good luck all.

[Nicola]

Hello. So sorry to hear these terrible reports. I had serotonin syndrome thus withdrew overnight from antidepressants. No need here to tell my story......years later the nerve damage remained which I could no longer take. Pregablin has saved my life I take 50mg three times a day for the nerve pain.
I wish all of you a safe and slow withdrawal go v v v v slowly do not rush . Ask your doctor if you can open the capsule to take a v small amount towards the end. Hey guys it's your body your wellbeing. I know what a fast withdrawal can lead to in my case this damned nerve pain.One day I hope to be off pregablin but my withdrawal will be so slow.
Take care.

[Erha]

I've been on Lyrica for nearly a decade for Fibromyalgia. I had tachycardia before starting, so I can't tell if it's currently a side effect or my normal heart; however, after 1.5 weeks, the night sweats are horrible.

I'm also having great trouble sleeping, which I assume contributes to mood swings. Other symptoms are blurry vision, lack of appetite, and weight loss; no surprise there if I can't eat. I've decided to up my physical training regiment of yoga and walking/running, which helps.

My top question is, how long does this last? I read somewhere "a few weeks," but does that represent 2 weeks or 20? I'd love to read up on those who no longer have withdrawal symptoms. How long did it take you?

Cheers.