Tolerance

Tolerance occurs when repeated exposure to a drug reduces its effectiveness, meaning higher doses are required to achieve the same pain relief.

This is most commonly seen with opioid medications, where receptor downregulation and cellular adaptations reduce the body’s responsiveness over time. Tolerance can complicate long-term treatment plans, making pain harder to control while increasing the risk of side effects.

Differentiating tolerance from disease progression or opioid-induced hyperalgesia (increased pain sensitivity due to opioids themselves) is critical in practice. Management strategies include rotating medications, lowering doses or combining drugs with non-pharmacological interventions. By using multimodal approaches — blending medication, physical therapy and interventional options — clinicians can reduce reliance on escalating doses and improve long-term pain control.