Ketamine Infusion for Peripheral Neuropathic Pain in a Pediatric Multivisceral Transplant Patient

Ketamine has been described as a potential treatment modality for a variety of neuropathic pain conditions.¹ Its primary mechanism of action is through noncompetitive nonselective antagonism at the N-methyl-d-aspartic acid (NMDA) receptor, although this single pharmacologic property does not fully explain the prolonged analgesic effects, which often significantly outlast ketamine’s half-life. Secondary mechanisms of action may contribute to the overall clinical impact of ketamine, as other NMDA antagonists such as magnesium do not generally exhibit the same neuropathic pain reduction and overall clinical effect.

Ketamine has conventionally been used for anesthetic induction, sedation, and for providing rapid analgesia. More recently, however, physicians are recognizing its use in other treatment protocols.³ While the published literature does not identify a gold standard treatment algorithm or infusion protocol for ketamine, a variety of low-dose ketamine infusion treatment regimens have been described for a litany of medical and psychiatric indications within the past several years; these are supported by case studies, metanalyses, and clinical trials.¹

Medical and psychiatric conditions being explored for ketamine use include:

• anxiety
• migraine
• post-traumatic stress disorder (PTSD)
• treatment-resistant depression
• substance use disorder
• tinnitus
• a range of neuropathic pain conditions, including peripheral neuropathies, complex regional pain syndrome (CRPS), fibromyalgia, and phantom limb pain

As of this writing, there are approximately 1,000 active ketamine trials registered on www.clinicaltrials.gov related to the non-trad­itional uses of ketamine.

Particular chemotherapeutic and immunosuppressive medications are a known cause of peripheral neuropathy.⁴˒⁵ This neuropathy can demonstrate unexpected onset and rapid escalation. Immunosuppressive medication classes that have been linked with the development of peripheral neuropathies include but are not limited to tumor necrosis factor-α (TFA-α) inhibitors, interferons, disease-modifying anti-rheumatic drugs (DMARDs), and calcineurin inhibitors.⁶

Although there are several pharmaceutical agents approved to reduce neuropathic pain, the effectiveness of available agents is often limited, leading to unacceptable levels of pain and diminished quality of life. As a known neuropathic analgesic, ketamine infusions should be considered when treating refractory neuropathic pain. Consider the following case example.

Patient Presentation

A 20-year-old female, status post multivisceral transplant secondary to small bowel ischemia, presented in 2018. Her case was complicated by repeat strictures and obstructions necessitating more than 20 exploratory laparotomy surgeries in the prior 3 years. (She had received hydromorphone IV PRN and fentanyl IV infusion prior to our treatment). Our pain team was consulted for discussion of opioid-sparing interventions.

The patient’s primary complaint was burning pain in the fingers and toes, which had been present for several months and had worsened in the prior several weeks. We were informed by the patient’s mother that the patient had received ketamine infusions as a hospital outpatient within the past 2 years to treat episodes of neuropathic pain secondary to her immunosuppressive medications, prescribed secondary to her transplant.

The patient was also seen by the pediatric psychology team who noted that her profile reflected severe depression (Beck Depression Inventory-II), severe anxiety (Beck Anxiety Inventory), and low quality of life measures (PedsQL Gastrointestinal Symptoms Module Young Adult Report).

The patient required admission to the pediatric ICU after presenting with vomiting, shortness of breath, abdominal pain, and respiratory distress. She was diagnosed with recurrent small bowel obstruction and required significant intravenous opioids for pain control. Multidisciplinary team members including transplant surgery, pediatrics, and PICU agreed with our recommendations for a trial of IV ketamine for symptomatic pain management, administered as two infusions on consecutive days with dosages (one at 0.2 mg/kg/hr and one at 0.4 mg/kg/hr for 5 hours each (total of 62 mg and 124 mg, respectively).

Outcome

Following the ketamine infusions, the patient and her family reported less pain, improved sleep, and a decrease in rescue analgesic use. She stated that “for the first time in weeks pain was not the first thing I thought of when I woke up.” The patient appeared more alert, conversational, and energetic on exam, and her parents expressed that her mood subjectively improved. The patient endorsed that the neuropathic pain in her hands/fingers and feet/toes, previously self-reported as 10/10 was now consistently less than 5/10. She reported that her overall pain was improved, including her visceral abdominal pain.

Overall, both patient and caretakers responded favorably to the ketamine infusion. The patient denied any significant nausea or other side effects including sedation or alteration in consciousness. As the patient demonstrated a history of resistant neuropathic pain along with her repeated inpatient care, the care team inquired as to whether these treatments could be made available with each future admission or perhaps even arranged as an outpatient analgesic therapy.

This case report demonstrates that ketamine has the potential to benefit neuropathic and visceral types of pain, with secondary improvements on sleep, mood, and quality of life – especially in individuals with comorbid psychiatric disorders, although recognized contraindications have included active episode or history of schizophrenia as well as active psychotic symptoms. Low-dose ketamine infusion also proved to be opioid-sparing with a subsequent lack of adverse effects such as nausea or somnolence.

The United States has witnessed an explosive area of growth in outpatient ketamine clinics, treating both physical and psychiatric conditions from depression and PTSD, to pain. It is likely that there will be a need for treatment in both inpatient and outpatient settings, and whether there are any advantages to either will certainly depend on the training and experience of the providers.

Although currently scarce, much research into the outpatient administration of ketamine is underway and should help frame safe treatment guidelines. If the evidence is supportive, payers and policymakers should adopt this new therapy as an accepted and appropriate treatment.