Complex encephalopathy arising from the combination of opioids and gabapentin

Abstract

The interactions between opioids and gabapentin are more clinically relevant than ever. Prescriptions dispensed for gabapentin increased from 39 million in 2012 to 64 million in 2018 in the USA and are ever increasing. Authors present a challenging case of these interactions. A 58-year-old man presented to the emergency department with acute respiratory failure and altered mental status. He was on high dose opioids and gabapentin as prescription medications. Despite full intensive care support and resolution of his respiratory failure with non-invasive positive pressure ventilation, the patient did not regained consciousness. After ruling out other causes, the diagnosis of gabapentin withdrawal was considered. Gabapentin was administered by a nasogastric tube that quickly resulted in a reversal of his symptoms. We concluded that severe gabapentin withdrawal should be considered in patients on higher doses of gabapentin when it is stopped abruptly. In such patients, gabapentin should be replaced. As most patients are unable to swallow in this situation and intravenous formulation is not available, nasogastric tube can be used for replacement.

Background

The interactions between opioids and gabapentin are more clinically relevant than ever. Prescriptions dispensed for gabapentin increased from 39 million in 2012 to 64 million in 2018 in the USA.¹ The only US Food and Drug Administration (FDA) approved indications are post-herpetic neuralgia in adults and as adjunctive therapy in the treatment of partial onset seizures, with and without secondary generalisation.² A significant proportion of gabapentin use remains off-label or non-FDA approved for multiple indications. In the USA, 95% of gabapentin prescribed was found to be for off-label use in managed medicaid populations.³

Studies are also pointing towards the fact that gabapentin misuse is specific to opioid use disorder population.^{1 4 5} In a recently published population-based case control study, it was found that 56% of gabapentin users were also taking opioids.¹

As a result, more patients are presenting to hospitals with the combination of opioids and gabapentin. Knowing the interplay of these medications helps make the right decisions in management. With this background, we present an interesting case of complex encephalopathy resulting from use of opioids and gabapentin. We hope to point out challenges and solutions associated with the case.

Case presentation

A 58-year-old man presented to the emergency department with acute respiratory failure and altered mental status. According to his wife, the patient had become less responsive, somnolent and confused over a period of 3 days. He suffered from chronic neck pain and back pain and has a spinal cord stimulator in place. Additionally, for pain, he was on extended release morphine sulfate 60 mg two times a day, oxycodone/acetaminophen 10/325 mg four times a day as needed and gabapentin 1000 mg three times a day. His other home medications included metformin, insulin with meals, omeprazole, valsartan, levothyroxine and niacin. No other medicine were noted to have significant interaction with opioids. His past medical history was notable for obstructive sleep apnea not on therapy, chronic obstructive pulmonary disease not on oxygen, type 2 diabetes mellitus, hypothyroidism and chronic back pain. He had a medical history of colovesical fistula that was surgically repaired. Social history was remarkable for 35-pack year smoking and he was not an alcohol user.

The patient was unable to provide a clear medical history at admission, so it was obtained from his wife. She reported that patient was taking his pain medications regularly along with his gabapentin. She also stated that patient was using all his as needed medications and took an extra dose of 60 mg of extended release morphine sulfate, 3–4 hours before coming to the hospital. She reported no fever, sputum production, cough, focal weakness, chest pain, syncope or palpitations. Emergency medical service personnel who responded to an emergency call found the patient having altered mental status and increased work of breathing. They placed the patient on a non-rebreather mask and administered 0.2 mg naloxone intravenously with partial response.

Initial evaluation in the emergency room showed his vitals with his blood pressure of 125/64 mm Hg, respiratory rate 14/min, oxygen saturations dropped to 83% on room air and were noted to be above 90% with a non-rebreather mask, pulse 70/min, temperature 98.3°F. The physical examination was notable for general confusion with intermittent agitation. Patient was obese with a body mass index of 32. Pupils were miotic. Neck was supple and breath sounds were diminished without any adventitious sounds. Heart sounds were normal without rub, murmurs or gallops. Abdomen was soft, non-tender and there was no evidence of florid volume overload.

Patient’s initial blood gas was consistent with acute respiratory acidosis. CT scan of the brain without contrast was negative for acute pathology. Ammonia level was 57 mcg/dL. D-dimer was found to be 7.24 μg/mL and patient had mild degree of acute renal failure. His baseline creatinine was 1.2 mg/dL and he presented with a creatinine of 1.57 mg/dL. Urine toxicology screen was positive for opioids with oxycodone reported separately as well. He was placed on naloxone drip and bi-level positive airway pressure (BiPAP) in the emergency department. Subsequent gases did not show considerable improvement in emergency department likely because patient was intermittently lethargic and agitated and was not wearing BiPAP consistently. A decision to admit the patient in intensive care unit (ICU) was made.

Patient’s gabapentin was discontinued at admission because of his lethargy and acute respiratory failure. In ICU, subsequent chest X-rays remained negative. As per ICU notes, patient was persistently encephalopathic despite naloxone drip. Ventilation–perfusion scan done as a result of respiratory failure and elevated D-dimer was low probability for pulmonary embolism. Empiric intravenous antibiotics (vancomycin and piperacillin–tazobactam) for possible pneumonia were initiated. After 48 hours of admission, patient started developing fevers up to 101.2°F, while still remaining encephalopathic. Intermittent fever spikes continued in ICU. This led to the addition of intravenous acyclovir to his drug regimen to broaden the coverage for possible herpes simplex encephalitis while a lumbar puncture was done. Cerebro spinal fluid (CSF) results showed no pleocytosis and no evidence of an infectious central nervous system (CNS) process. Inflammatory markers including procalcitonin and C reactive protein (CRP) were normal. CSF and blood cultures did not show any growth.

Second day in ICU, the patient started showing improvement in his respiratory status without any significant mental status improvement. His blood gases showed a considerable improvement with correction of respiratory acidosis. His prolonged apneic episodes were better.

His renal function improved to normal. He was placed on 8 L oxygen via nasal cannula and subsequently went on ambient air. Low dose morphine was started to prevent opioid withdrawal. Intermittent BiPAP was being continued. His echocardiogram showed preserved ejection fraction and no significant pulmonary hypertension. At this time, patient was transferred out of ICU to step down unit. Despite noted improvement in respiratory status patient remained encephalopathic. His CT brain, ECG, white cell count, CSF results, electrolytes and his liver and kidney numbers were within normal limits. Neurology team wanted to rule out subclinical seizures.

First day on step-down unit and third day into admission, patient started exhibiting flailing movements of the limbs and exhibited increased motor activity. No improvement was seen in mental status so far and patient was not following commands, was moaning and restless. His abnormal motor activity resembled akathisia while he was still not responding to verbal commands or touch. He was withdrawing to pain. Patient was so agitated that he had to be restrained to avoid injury.

Investigations

The white cell count, haemoglobin and platelet count were within normal limits.

Patient had mildly elevated creatinine at 1.57 mg/dL from his baseline at 1.2 mg/dL.

His blood urea nitrogen was 30 mg/dL.

Electrolytes and liver numbers were normal.

Ammonia 57 μg/dL.

D-Dimer 7.24 μg/mL.

Arterial blood gas initial pH 7.24, PaCO₂ 60 mm Hg.

CSF results: no white cells seen.

Blood cultures: no growth.

CSF cultures: no growth.

Differential diagnosis

The common causes of development of delirium and confusional states in individuals include drug use, withdrawal states, medication side-effects, infections, metabolic derangements, brain disorders such as seizures, CNS infections, systemic organ failure and physical disorders such as electrocution, burns and hypothermia. Our patient had fevers and altered mental status. Development of such symptoms in an individual often leads to workup for infectious causes of encephalopathy including encephalitis. The development of fevers with delirium often leads to the consideration of alcohol withdrawal but not with other commonly used psychotropic drugs.

Our patient was not on any new medicine. His workup was negative for sepsis and meningitis. Initial labs were consistent with respiratory acidosis and mild acute renal failure, which were corrected in ICU in the first 2 days. His urine toxicological screen was negative for any illicit substances. There was no history of burns, hypothermia, electrocution or alcohol use. An electroencephalogram ruled out sub-clinical seizure activity. As the patient was exhibiting restlessness resembling akathisia, a psychiatry input was taken.

Treatment

The psychiatrist spoke with patient’s family and requestioned about any drug use. It was noted that patient had similar symptoms a year ago when he missed taking gabapentin because of a procedure. This led to a concern for gabapentin withdrawal contributing to his symptoms and diagnosis of gabapentin withdrawal was included in differential. Because of absence of intravenous formulation and patient’s inability to swallow, a nasogastric tube was placed immediately and 300 mg gabapentin was given. Soon after patient’s abnormal motor activity subsided, and he was much calmer. Thereafter, the dose of gabapentin was increased to 600 mg every 8 hours via peg tube. Nurses noted patient to be more cooperative in 12 hours and restraints were taken off. Next morning patient was found to be oriented to time, place and person and was noted to have a remarkable recovery.

Outcome and follow-up

His antimicrobials were discontinued, and he was discharged home on gabapentin 600 mg three times a day. He was also educated to not stop gabapentin abruptly in the future. Opioids were discontinued at discharge and patient was referred to his primary medical doctor to get a pain management consultation. The temporal relationship between the development of symptoms after discontinuing gabapentin and quick recovery after initiating gabapentin suggested that the patient had gabapentin withdrawal.

Discussion

This particular case presents an interesting opportunity to observe the clinical interaction between opioids and gabapentin. The initial presentation with acute respiratory acidosis was likely result of inadequate ventilation. As per Eckhardt et al, both pharmacokinetic and pharmacodynamics interactions between morphine and gabapentin lead to increased acute analgesia.⁶ Studies have pointed out dose dependent synergistic interactions between opioids and gabapentin in animal models as well.⁷ Our patient was on high doses of opioids and gabapentin. He took an extra dose of extended release morphine as well. On admission, he was found to be in mild renal failure as seen on his labs. All these factors along with the fact that opioids and gabapentin can potentiate each other may have lead to initial state of presentation. To reverse opioids, naloxone was used, as is done in general practice. A very recent study by Yung et al pointed out that gabapentin may pose a risk factor for over sedation when combined with opioids, leading to increased naloxone use.⁸

Gabapentin does not bind to proteins and has a half-life of 5–7 hours. Withdrawal symptoms can appear from 12 hours to 7 days after discontinuation.⁹ On an average, gabapentin withdrawal are seen in patients taking doses on an average above 3000 mg/day.⁹ Approximately 75% of cases stopped gabapentin abruptly before developing withdrawal symptoms.¹⁰ In our case, the patient started developing severe symptoms of withdrawal at about day 3 of presentation. The common signs and symptoms of gabapentin withdrawal syndrome include development of hypertension, tachycardia, agitation, delirium, confusion, anxiety, combativeness, hallucinations, disorientation, paranoid delusions, tremor and increased muscle tone.^11–14 Critical withdrawal symptoms including status epilepticus and catatonia have also been reported with gabapentin withdrawals.^{15 16} Our patient exhibited fever and flailing movements of the limbs which resembled akathisia. He was not able to follow commands and he was responding to pain by withdrawing. He was moaning and was restless. The patient did not present with ususal symptoms of gabapentin withdrawal probably because his withdrawal state appeared in presence of opioid overdose. There is not much literature on gabapentin withdrawal state while recovering from opioid overdose. Our patient did have fever without features of an underlying infection. Case report by Pittenger et al reported patient having fever as a part of withdrawal syndrome.¹⁷ His flailing movements and restlessness subsided after gabapentin was replaced. See et al have reported a case of akathisia from gabapentin withdrawal before.¹⁸ We believe this is the second reported case in literature. Interestingly, gabapentin is being seen as a potential treatment for anti-psychotic medication induced akathisia.¹⁹

To our knowledge, there is only one case report before that mentions use of nasogastric tube for gabapentin replacement in severe withdrawal in critical care settings.²⁰ Gabapentin can be replaced safely in most of the cases other than any absolute contraindication like multiorgan hypersensitivity-drug reaction with eosinophilia and systemic symptoms syndrome and is thought to be the most effective treatment.²

Finally, this case points out the risks involved with treating patients with high dose opioids and gabapentin simultaneously. Stannard et al pointed out that clinically meaningful pain relief with gabapentinoids is achieved in fewer than 20% of patients with discrete diagnoses.^{21 22} We feel the severity of gabapentin’s ability to cause life-threatening interactions with other pain medications and serious withdrawals is under appreciated. Further studies are needed to establish safety in off-label situations. Best practice scenarios should be instituted to stop misuse of this medicine.

Learning points.

• Severe gabapentin withdrawal should be considered in patients on higher doses of gabapentin when it is stopped abruptly. In such patients, clinician should replace gabapentin.

• If patients are unable to swallow, nasogastric tube can be used for replacement.

• It is important to educate doctors and patients to not to stop gabapentin abruptly to minimise development of this withdrawal state.