A 2020 review article published in Frontiers in Pharmacology (doi:10.3389/fphar.2020.599721) highlights the expanding role of ketamine in the treatment of cancer-related and chronic non-cancer pain. The authors examine a range of clinical and mechanistic evidence that supports ketamine’s use as an effective, multi-modal analgesic for patients with severe, refractory pain — especially when conventional opioids and adjuvants prove insufficient.
As healthcare providers seek safer, more effective alternatives to long-term opioid therapy, ketamine offers a unique therapeutic profile, combining analgesic potency, rapid onset, NMDA receptor antagonism, and utility across various routes of administration.
Overview of the Review
- Journal: Frontiers in Pharmacology, 2020
- Article Type: Narrative review
- Focus Areas:
- Ketamine in cancer pain, including neuropathic and breakthrough pain
- Ketamine for chronic non-cancer pain (CNCP), including fibromyalgia and complex regional pain syndrome (CRPS)
- Mechanisms of action and clinical protocols
- Safety, tolerability, and emerging evidence
Clinical Applications in Cancer Pain
1. Breakthrough and Neuropathic Pain
- Ketamine is used as a rescue agent when standard opioids (e.g., morphine, fentanyl) are inadequate
- Particularly effective for neuropathic pain, which is less responsive to opioids
- May reduce the required opioid dose, limiting side effects like sedation, constipation, and respiratory depression
2. Routes of Administration
- Intravenous (IV): Preferred for rapid effect in acute settings
- Subcutaneous (SC): Useful for outpatient/home care
- Oral, intranasal, and topical forms under investigation
3. Opioid-Sparing Effects
- Ketamine enhances opioid analgesia through synergistic mechanisms
- Downregulates NMDA receptor-driven central sensitization
- Prevents or reverses opioid-induced hyperalgesia (OIH)
Ketamine in Chronic Non-Cancer Pain (CNCP)
1. Complex Regional Pain Syndrome (CRPS)
1. Complex Regional Pain Syndrome (CRPS)- Evidence supports ketamine infusions as a second-line treatment for CRPS
- Long-lasting relief (weeks to months) reported in resistant cases
2. Fibromyalgia and Neuropathic Syndromes
- Small-scale trials show improvements in pain, fatigue, and quality of life
- May benefit patients with central sensitization and widespread allodynia
3. Intractable Back and Spinal Pain
- Ketamine used in cases of failed back surgery syndrome (FBSS) or radiculopathy
- Provides analgesia without the motor side effects of spinal cord stimulators
Mechanisms of Action
Ketamine’s multimodal analgesic effects stem from its ability to:
- Antagonize NMDA receptors, preventing long-term potentiation of pain pathways
- Modulate glutamate, GABA, dopamine, and opioid systems
- Promote neuroplasticity and synaptogenesis, supporting functional recovery
- Activate descending inhibitory pain pathways via the periaqueductal gray (PAG)
Additionally, ketamine influences inflammatory cascades and may reduce central glial activation, further decreasing chronic pain amplification.
Dosing and Administration Protocols
- Acute inpatient dosing: 0.1–0.5 mg/kg IV bolus or infusion
- Outpatient maintenance: 0.2–0.3 mg/kg IV every 1–2 weeks
- Adjuvant therapy: Often combined with lidocaine, midazolam, or clonidine for enhanced efficacy and reduced side effects
- Titration is highly individualized, based on pain phenotype, response, and psychiatric history
Safety and Side Effects
Ketamine is generally well tolerated at sub-anesthetic doses. Common side effects include:
- Mild dissociation
- Nausea or dizziness
- Transient hypertension or tachycardia
- Rarely, hallucinations or agitation (mitigated with benzodiazepines)
No serious adverse events were reported in most clinical studies reviewed. When used in monitored environments, ketamine’s risk profile is low compared to chronic opioid therapy.
Limitations and Future Directions
- Standardized protocols are lacking, with variation in dose, frequency, and administration method
- Larger RCTs needed to confirm long-term benefits and optimal scheduling
- Exploration of oral and intranasal formulations could increase access
- Need for guidelines on use in palliative care, pediatrics, and elderly populations
Conclusion
The 2020 Frontiers in Pharmacology review highlights ketamine as a versatile and underutilized tool in the management of both cancer-related and chronic non-cancer pain. Its ability to modulate pain at multiple neurophysiological levels, reduce opioid dependence, and provide rapid relief makes it a compelling choice for complex pain cases.
As the opioid crisis continues and the demand for integrative pain management grows, ketamine is poised to play a central role in multimodal analgesia — especially for patients who have run out of conventional options.
Reference
Matsuoka N, Sumitani M, et al. (2020). Ketamine Use for Cancer and Chronic Pain Management. Frontiers in Pharmacology. Read Full Article
