Opioid Tolerance: Cancer Pain

Advanced, Clinical Subspecialties

Opioid tolerance is a phenomenon that occurs when administering a fixed dose of an opioid results in decreasing analgesia, requiring higher doses to achieve the same effect over time. This manifestation is thought to involve the N-methyl-D-aspartate (NMDA) receptor, though the mechanism is not fully understood. Cancer patients are at particularly high risk of developing opioid tolerance, especially when the cancer has created a pain source, affects pain transmission in the central nervous system, and creates a central perception of pain in the brain. Cancer generates pain via local invasion and metastasis, creating spinal cord compression and plexopathies, or requiring chemotherapy and/or radiation that generates mucositis and neuropathic side effects.  Opioids are a first-line treatment for cancer pain, and an estimated 70-95% of patients can live relatively pain-free with a combination of antineoplastic treatments, NSAIDs, opioids, and other oral analgesics. Though the lowest effective dose of opioids should be used to minimize drug side effects, cancer patients with particularly painful disease courses can be gradually increased to large doses to achieve acceptable pain perception and functionality.

The FDA defines opioid tolerant patients as those that receive 60 oral morphine equivalents per day for at least one week. When a patient is suspected of becoming tolerant to one opioid, progression of the underlying cancer should always be considered first. When opioid tolerance is present, a medication rotation can be helpful. This is done by switching one opioid for another and reducing to half the equianalgesic dose, then titrating to an adequate analgesic effect. This often leads to improved analgesia at lower doses of the new opioid with decreased side effects, and is thought to be the result of incomplete tolerance. Though not fully understood, the mechanism by which an opioid rotation works may be related to each opioid having different affinities for the mu-receptor and other opioid receptor subtypes.


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Brett Toimil, MD