Subanesthetic, subcutaneous ketamine infusion therapy was significantly effective, well-tolerated and also reduced the use of opioids in patients with chronic nonmalignant pain

Chronic nonmalignant pain significantly reduces function and quality of life of patients affected by it. The pain needs to be adequately managed to avoid further complications. Neuropathic pain (NP) is one of the common occurrences in such patients and patients fail to improve with traditional pain killers and opioids. NP is caused due to nerve damage and patients usually experience spontaneous pain, hyperalgesia and allodynia.

Ketamine is general dissociative anaesthesia, mainly used in minor surgical and diagnostic procedures. It acts centrally as well as peripherally. It is primarily an NMDA receptor antagonist but also plays a role in the inhibition of Na+ and K+ channels and reuptake of dopamine and serotonin. It has also shown some effects on α-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid and kainate and γ -aminobutyric acid receptors. Chronic noxious input to the dorsal horn cells causes magnesium removal from the NMDA receptors and their activation by glutamate. Hyperalgesia and allodynia are caused by the prolonged depolarization of spinal neurons resulting in central sensitization. Ketamine binds to NMDA receptor and reduces NMDA-mediated nociceptive responses in dorsal horn neurons. Ketamine may reduce pain by antagonizing NMDA receptors, reduces tolerance of opioids, improves the sensitivity of opioid receptors and overcomes opioid-induced hyperalgesia.

Currently, oral or sublingual ketamine formulations are not available for commercial use, but compounding pharmacist may formulate it. Previous research has suggested the superior bioavailability of sublingual formulation (40%) as compared to the oral formulation of ketamine. In both the routes, the analgesic activity is attributed to its metabolite, norketamine. After oral and sublingual administration, the ratios of mean norketamine/ketamine area under the plasma concentration-time curve from baseline to 8 hours were 2.1 and 5.

Rationale behind research: Despite of being in use for many years for pain management, the long term effectiveness of ketamine has not been tested for the management of chronic nonmalignant pain. 

Objective: The present prospective non-randomized non-blinded study was conducted to evaluate the effectiveness, toxicity and reduction in opioid use after administration of subanesthetic subcutaneous ketamine infusion therapy in chronic nonmalignant pain management.

Study Outcomes:

Baseline: Patients’ demographic characteristics, pain site, pain duration, pain intensity, use of opioids and other analgesics were assessed at the baseline.

Outcomes:

• Pain intensity: evaluated using Numeric rating scale (NRS) (0–10 point verbal response score with 0 indicating no pain and 10 being the worst pain imaginable)
• Use of opioid medication: evaluated using mean morphine equivalent daily dose (MEDD)
• Adverse effects

Time Points:

• Baseline and between 3 months and 6 years

Outcomes:

• Pain intensity: A significant reduction in pain intensity measured by the NRS was observed from a mean of 6.38 before ketamine infusion to 4.6 after ketamine infusion (Figure 1)

Figure 1: Reduction in pain intensity measured by the NRS before and after ketamine infusion

• Use of Opioid medication: There was a significant reduction in mean morphine equivalent daily dose (MEDD) from 216 mg/day before ketamine infusion to 89 mg/day after ketamine infusion

Figure 2: Reduction in opioid dose before and after ketamine infusion

• Adverse effects: There were common but mild adverse effects. The adverse effect experienced by the majority of the patients (46%) was lightheadedness and dizziness. 25% of patients experienced tiredness and sedation, 12% experienced headaches while others experienced hallucinations, vivid dreams, urinary tract infection, and diplopia.  The adverse effects were easily manageable.

The patients who responded well to the inpatient infusion therapy were given ongoing maintenance with sublingual ketamine lozenges 100 mg (commencing dose: 25 mg three times a day). These subjects were followed up by a telephone consultation questionnaire between 3 months and 2 years. Patients (31%) who used lozenges post ketamine infusion did not consume opioids compared to 6% patients not on lozenges. 11% of the total patients who declined lozenges had increased their dose of opioids.

The present study demonstrated long term efficacy of subanesthetic subcutaneous ketamine infusion therapy for treating chronic nonmalignant pain. The study also reported that ketamine was well-tolerated and caused a significant reduction in the use of opioids.

There is a lack of published evidence supporting the long-term use of opioids in chronic nonmalignant pain. Also, presently available medications are not sufficient enough to manage pain in the context of central sensitization. Ketamine infusion therapy could be valid for those patients who have failed numerous pharmacological and cognitive-behavioural therapy options. Ketamine lozenges, on the other hand, were able to reduce the use of opioids in this class of patients. Overall, ketamine infusion therapy as well as ketamine lozenges, both demonstrated effectiveness in treating chronic nonmalignant pain without considerable adverse effects. However, to study the importance of treatment effect shown by ketamine lozenges, blinded RCTs are required to be conducted.