More than half of patients with mastocytosis experience musculoskeletal pain, caused by mediators released from stimulated mast cells, the presence of bone structure disorders or infiltration of bone and soft tissues by mast cells. In the treatment of pain drugs capable of inhibiting mast cells degranulation, such as H1 receptor antagonists or H2 receptor antagonists, in combination with analgesics and coanalgesics should be administered. However, the use of non-steroidal anti-inflammatory drugs and opioid analgesics are associated with the risk of symptoms related to the degranulation of mast cells, including anaphylactic reaction. For this reason, drugs with the lowest potential to activate mast cells should be preferred. The article presents a case of systemic mastocytosis complicated by severe pain of bones and joints, requiring a chronic therapy with strong, controlled-release opioids. Transmucosal fentanyl buccal tablets have been used to treat breakthrough pain, providing good control of incidental pain triggered by physical activity and thus ensuring the opportunity to work despite the disease.