We conducted a feasibility study of sublingual methadone for breakthrough cancer pain, to determine whether a larger, randomized trial was warranted, and to identify a study design that would be likely to succeed. From approximately 1930 patients in the initial pool, nine patients were enrolled. Five patients completed the study, generating data on 83 discrete episodes of breakthrough cancer pain at optimal dose. Mean pain intensity dropped by 1.7 points (on a 10 point numerical scale) within 10 min of sublingual methadone administration, and by 3.2 points after 15 min. No serious or severe toxicity was encountered. Based on the results of this feasibility study, a larger randomized clinical trial of sublingual methadone for breakthrough cancer pain using this trial model would not be successful. Extensive information obtained from small numbers of carefully studied patients provides proof of concept that sublingual methadone is effective, safe, and well tolerated.
Portenoy RK and Hagen NABreakthrough pain: definition, prevalence and characteristics. Pain1990; 41: 273-281.
2.
Mercadante S. , Radbruch L., Caraceni A., et al. Episodic (breakthrough) pain: consensus conference of an expert working group of the European Association for Palliative Care. Cancer2002; 94: 832-839.
3.
Fine PG and Busch MACharacterization of breakthrough pain by hospice patients and their caregivers . J Pain Symptom Manage1998; 16: 179-183.
4.
Portenoy RK, Payne D. and Jacobsen P.Breakthrough pain: characteristics and impact in patients with cancer pain . Pain1999; 81: 129-134.
5.
Zeppetella G. , O’Doherty CA and Collins S.Prevalence and characteristics of breakthrough pain in cancer patients admitted to a hospice . J Pain Symptom Manage2000; 20: 87-92.
6.
Cleary JFPharmacokinetic and pharmacodynamic issues in the treatment of breakthrough pain. Semin Oncol1997; 24: S16-S19.
7.
Zeppetella G.Opioids for cancer breakthrough pain: a pilot study reporting patient assessment of time to meaningful pain relief. J Pain Symptom Manage2008; 35: 563-567.
8.
Hagen NA, Biondo P. and Stiles C.Assessment and management of breakthrough pain in cancer patients: current approaches and emerging research. Curr Pain Headache Rep2008; 12: 241-248.
9.
Weinberg DS, Inturrisi CE, Reidenberg B., et al. Sublingual absorption of selected opioid analgesics. Clin Pharmacol Ther1988; 44: 335-342.
10.
Walker G., Wilcock A., Manderson C., Weller R. and Crosby V.The acceptability of different routes of administration of analgesia for breakthrough pain. Palliat Med2003; 17: 219-221.
11.
Portenoy RK , Taylor D., Messina J. and Tremmel L.A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clin J Pain2006; 22: 805-811.
12.
Rauck RL, Tark M., Reyes E., et al. Efficacy and long-term tolerability of sublingual fentanyl orally disintegrating tablet in the treatment of breakthrough cancer pain. Curr Med Res Opin2009; 25: 2877-2885.
13.
Rauck R., North J., Gever LN, Tagarro I. and Finn ALFentanyl buccal soluble film (FBSF) for breakthrough pain in patients with cancer: a randomized, double-blind, placebo-controlled study. Ann Oncol21: 1308-1314.
14.
Kress HG, Oronska A., Kaczmarek Z., Kaasa S., Colberg T and Nolte T. Efficacy and tolerability of intranasal fentanyl spray 50 to 200 microg for breakthrough pain in patients with cancer: a phase III, multinational, randomized, double-blind, placebo-controlled, crossover trial with a 10-month, open-label extension treatment period. Clin Ther2009; 31: 1177-1191.
15.
Vasisht N., Gever LN, Tagarro I. and Finn ALFormulation selection and pharmacokinetic comparison of fentanyl buccal soluble film with oral transmucosal fentanyl citrate: a randomized, open-label, single-dose, crossover study. Clin Drug Investig2009; 29: 647-654.
16.
Bruera E. and Sweeney C.Methadone use in cancer patients with pain: a review. J Palliat Med2002; 5: 127-138.
17.
Manfredi PL , Borsook D., Chandler SW and Payne R.Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations . Pain1997; 70: 99-101.
18.
Morley JS and Makin M.The use of methadone in cancer pain poorly responsive to other opioids . Pain Reviews1998; 5: 51-58.
19.
Ripamonti C. , Zecca E. and Bruera E.An update on the clinical use of methadone for cancer pain. Pain1997; 70: 109-115.
20.
Scholes CF, Gonty N. and Trotman IFMethadone titration in opioid-resistant cancer pain. Eur J Cancer Care (Engl)1999; 8: 26-29.
21.
Fisher K., Stiles C. and Hagen NACharacterization of the early pharmacodynamic profile of oral methadone for cancer-related breakthrough pain: a pilot study. J Pain Symptom Manage2004; 28: 619-625.
22.
Inturrisi CE , Portenoy RK, Max MB, Colburn WA and Foley KMPharmacokinetic-pharmacodynamic relationships of methadone infusions in patients with cancer pain. Clin Pharmacol Ther1990; 47: 565-577.
23.
Hagen NA, Fisher K. and Stiles C.Sublingual methadone for the management of cancer-related breakthrough pain: a pilot study. J Palliat Med2007; 10: 331-337.
24.
Hagen NA, Wu JS and Stiles CRA proposed taxonomy of terms to guide the clinical trial recruitment process . J Pain Symptom Manage40: 102-110.
25.
Hagen NA, Stiles C., Nekolaichuk C., et al. The Alberta Breakthrough Pain Assessment Tool for cancer patients: a validation study using a delphi process and patient think-aloud interviews . J Pain Symptom Manage2008; 35: 136-152.
26.
Dale O. and Hagen KBDespite technical problems personal digital assistants outperform pen and paper when collecting patient diary data. J Clin Epidemiol2007; 60: 8-17.
27.
Piasecki TM , Hufford MR, Solhan M. and Trull TJAssessing clients in their natural environments with electronic diaries: rationale, benefits, limitations, and barriers. Psychol Assess2007; 19: 25-43.
28.
Stone AA, Shiffman S., Schwartz JE, Broderick JE and Hufford MRPatient compliance with paper and electronic diaries. Control Clin Trials2003; 24: 182-199.
29.
Etter ML, George S., Graybiel K., Eichhorst J. and Lehotay DCDetermination of free and protein-bound methadone and its major metabolite EDDP: enantiomeric separation and quantitation by LC/MS/MS. Clin Biochem2005; 38: 1095-1102.
30.
Quan H., Stiles C., Biondo P., Fainsinger R., Hagen N. and Moulin D.Teleform usage in clinical trials: database management. Palliat Med2008; 22: 430.
31.
Rinck GC, van den Bos GA, Kleijnen J., de Haes HJ, Schade E. and Veenhof CHMethodologic issues in effectiveness research on palliative cancer care: a systematic review. J Clin Oncol1997 ; 15: 1697-1707.
32.
McMillan SC and Weitzner MAMethodologic issues in collecting data from debilitated patients with cancer near the end of life. Oncol Nurs Forum2003 ; 30: 123-129.
33.
Grande GE and Todd CJWhy are trials in palliative care so difficult?Palliat Med2000; 14: 69-74.
34.
Mitchell GK and Abernethy APA comparison of methodologies from two longitudinal community-based randomized controlled trials of similar interventions in palliative care: what worked and what did not?J Palliat Med2005; 8: 1226-1237.
35.
Ewing G., Rogers M., Barclay S., McCabe J., Martin A. and Todd C.Recruiting patients into a primary care based study of palliative care: why is it so difficult?Palliat Med2004; 18: 452-459.
36.
Cook AM, Finlay IG and Butler-Keating RJRecruiting into palliative care trials: lessons learnt from a feasibility study. Palliat Med2002; 16: 163-165.
37.
McWhinney IR , Bass MJ and Donner A.Evaluation of a palliative care service: problems and pitfalls. BMJ1994; 309: 1340-1342.
38.
Gaertner J. , Elsner F., Pollmann-Dahmen K., Radbruch L. and Sabatowski R.Electronic pain diary: a randomized crossover study. J Pain Symptom Manage2004; 28: 259-267.
39.
Lauritsen K. , Degl’ IA, Hendel L., et al. Symptom recording in a randomised clinical trial: paper diaries vs. electronic or telephone data capture. Control Clin Trials2004; 25: 585-597.
