1. Dominique A. Lossignola and Cristina Dumitrescu Current Opinion in Oncology 2010, 22:302–306 R2 박소영 /prof. 이재진

2. Introduction Breakthrough pain (BTP) In 1990, Russell K. Portenoy and Neil A. Hagen published a paper about breakthrough pain (BTP) associated with cancer pain transient exacerbation of pain occurring in a patient with otherwise stable pain receiving chronic opioid therapy BTP is distinguished from other pain syndromes because of its unique physiopathology, clinical and socio-economic importance and treatment considerations

3. Epidemiology Breakthrough pain occurs in approximately 50–95% of cancer pain patients The epidemiology of the BTP is also complex, different aspects that can define it investigation methods multiple perceptions and description used by the patients It must be emphasized that BTP has a socio-economic impact and is associated with higher medical costs because of repeated hospitalizations

4. Classification (1) Incident : in relationship with motor activity (sneezing, coughing, bladder spasm, etc.) (a) predictable in most of the cases, good response to treatment (b) unpredictable, less responsive to treatment because of its rapid escalation and the nonpretreatable characteristic

5. (2) Idiopathic : not associated to any known cause, often suggests a progressive cancer (3) End-of-dose : before a schedule or around-clock analgesic more gradual onset and a longer duration than the incident and idiopathic BTP

6. Characteristics of breakthrough pain a rapid onset of acute pain (less than 3 min) experienced one to four times a day lasting from seconds to hours caused by multiples factors (e.g., movements, cough, micturition, respiration, deglutition or unknown, e.g., neuropathic pain) on a co-existing chronic pain syndrome and adequate chronic treatment on an underlying progressive or disseminated cancer

7. Physiopathology somatic, visceral, or neuropathic pathophysiology Portenoy and Hagen on 63 patients, described a median of four episodes of pain/day, with a duration of 30 min 33% of somatic origin 20% of visceral one 7% of neuropathic mixed

8. BTP was related to 98% of the presence of the tumor, 20.8% to the therapy 2.3% to none of them The presence of this type of pain was also associated with different pain syndrome radiculopathy plexopathy syndrome vertebral lesion syndrome bone lesions

9. In a 2004 study on a group of 1095 cancerous patients 18% related to lung cancer 13% to breast cancer 10% to head and neck tumors 9.6% to gastrointestinal cancer 6% to prostatic cancer Other mechanisms intrinsic mechanisms related to the activity of wide dynamic range neurons (WDRN) with a low level of excitability the implication of N-methyl-D-aspartate (NMDA) receptors

10. Treatment

11. The goal of BTP management effective treatment of the persistent pain decrease the frequency and intensity of the BTP episodes Prevention of precipitating events is of concern such as antitussive medication for cough, limb orthotic for incident pain Nonopioid medications have to be considered Coanalgesics (antidepressants, antiepileptic drugs) Anesthetic procedures (spinal local anesthetic)

12. The use of the same opioid treatment for the baseline persistent pain easier titration of the around-clock dose A better management of opioid side effects Increasing opioid dose until adequate analgesia is achieved is often limited by the side effects (nausea (10%), somnolence(28%), dizziness (14%) and headache (5%))

13. The route of administration has also an increased value subcutaneous injections affect patient autonomy and social activity Sublingual morphine Bitter taste and the delayed onset of action rectal route be preferred only for the use of morphine and hydromorphone parenteral route of morphine avoided because of the technical and medical problems. Oral administration of morphine not recommended for the treatment of BTP owing to the particular kinetics

14. Morphine, oxycodone and the hydromorphone hydrophilic nature and extensive first-pass, the analgesic activity starts only 30 min after administration and lasts for at least 4 h Fentanyl potent and highly lipophilic, it is readily absorbed from the oral mucosa and rapidly crosses the blood–brain barrier

15. Only oral methadone and transmucosal fentanyl have a definite advantage Essential caution of of the use of methadone its long elimination half-life and great accumulation potential, with a toxicity result Antiepileptics are effective but are absolutely not useful in the acute onset of BTP Oral transmucosal fentanyl citrate (OTFC) was designed to achieve rapid analgesia and is the first drug specifically approved for treating breakthrough cancer pain 25% oral transmucosal absorption, 75% swallowed Initial dose is 100 or 200mg

16. Another formulation for fentanyl Fentanyl buccal tablets fentanyl nasal spray

17. Conclusion BTP remains a challenge especially among cancer patients An accurate diagnosis followed by a specific treatment is the key for an effective pain relief Oral (transmucosal, film, tablets) or intranasal fentanyl is the medication of choice The development of new formulations for fentanyl is certainly the key to improve BTP management.